Sacubitril intermediate and preparation method thereof

ABSTRACT

The present invention relates to a sacubitril intermediate and a preparation method thereof. The sacubitril intermediate disclosed herein can be prepared by a deprotection reaction of a compound. In addition, the intermediate can be used as a raw material to synthesize sacubitril. The method disclosed herein has advantages of easily obtained raw materials, simple preparation process, low cost, environment friendly, and etc., which is very suitable for industrial production.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part application of the International PatentApplication No. PCT/CN2017/075097, filed Feb. 28, 2017, which claimspriority to Chinese Patent Application No. 201610111396.6, filed Feb.29, 2016, both of which are incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

The present invention relates to the medical and chemical industryfield, more specifically to a sacubitril intermediate and a preparationmethod thereof.

BACKGROUND OF THE INVENTION

Sacubitril, the chemical name is4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoicacid, the structure is as following:

U.S. FDA approved the anti-heart failure (anti-HF) drug Entresto (knownas LCZ696) on July, 2015, which is a complex of the angiotensin IIinhibitor valsartan and the enkephalinase inhibitor sacubitril.Valsartan can improve vasodilation and stimulate the body to excretesodium and water, and sacubitril can block the mechanism of action oftwo peptides that threaten to lower blood pressure, thus LCZ696 is knownas a dual inhibitor of angiotensin II receptor and enkephalinase, itsclinical manifestation is a unique mode of action, which is superior tothe standard drugs with respect to antihypertensive effect and theefficacy of reducing heart failure.

Some methods of preparing sacubitril are disclosed in the prior art,such as:

Patent application WO2008031567A1 disclosed a method of preparingbiphenyl butyric acid substituted on 4 position amino or derivativethereof by using biphenyl propanol substituted on 2 position amino asstarting materials, which was oxidized to aldehyde, and the aldehyde wassuffered from Witting reaction to give biphenyl butenoic acidsubstituted on 4 position amino or derivative thereof, and the biphenylbutenoic acid substituted on 4 position amino or derivative thereof wassuffered from a reduction reaction under H₂ in the presence oftransition metal of group 7, 8 and 9 in the chemical periodic table ascatalyst and a chiral ligand, and then chiral separation to givebiphenyl butyric acid substituted on 4 position amino or derivativethereof. The product can be converted to sacubitril. The process of themethod is depicted as follows:

Patent application WO2008083967A2 disclosed a method of preparingsacubitril using 2-carbonylproline as a starting material, which wassuffered from carboxy activation, biphenyl substitution, carbonylreduction, chiral methylation, ring opening reaction and amidecondensation and so on to give sacubitril. The reaction is depicted asfollows:

The synthetic routes disclosed in patent applications WO 2008031567A1and WO 2008083967A2 have some differences in the use of the rawmaterials, forming method of chirality and order of unit reactions,however, there are disadvantages such as difficulty in obtaining chiralraw materials, many reaction steps, expensive chiral catalytic reductioncatalysts, poor stereoselectivity, and repeated use of carboxy or aminoprotection and deprotection, it is difficult to achieveindustrialization smoothly.

Chiral induction agent (S)-1-(α-aminobenzyl)-2-naphthol (S-betti Base)with 2R-methyl-4-oxo-butanoic acid were suffered from cyclization,addition, debenzylation, ring opening, esterification and amidation andso on to give sacubitril disclosed in CN104557600A. The process isdepicted as follows:

The process of preparing sacubitril has disadvantages of expensive andnot readily available S-betti Base and chiral starting materials,preparation of Grignard reagent before addition reaction, strictreaction conditions, uncontrollable, and more cumbersome syntheticroute.

SUMMARY OF THE INVENTION

In a first aspect, provided herein are an intermediate for preparingsacubitril shown as a compound of Formula (V), and a preparation methodof the compound of Formula (V);

wherein

R₁ may be phenyl, methoxy, hydroxy, chloro, bromo, iodo, mesylate(—OMs), triflate (—OTf) or 4-methylbenzenesulfonate (—OTs);

R₂ may be

R₃ may be H, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl. Wherein —(C₁-C₄)alkylin some embodiments may be methyl, ethyl, n-propyl, i-propyl, n-butyl,t-butyl. Wherein —(C₁-C₄)alkyl-aryl in some embodiments may be benzyl oroptionally substituted benzyl.

R₄ may be H, —(C₁-C₄)alkyl, —(C₃-C₆)heterocyclyl, —(C₁-C₄)alkyl-aryl,trimethylsilyl, triethylsilyl or t-butyldimethylsilyl. Wherein—(C₁-C₄)alkyl in some embodiments may be methyl, ethyl, n-propyl,i-propyl, n-butyl, t-butyl. Wherein —(C₁-C₄)alkyl-aryl in someembodiments may be benzyl or optionally substituted benzyl.

In a second aspect, provided herein are two methods of preparingsacubitril from a compound of Formula (V), the two methods haveadvantages of easily obtained raw materials, simple preparation process,low cost and friendly environment, and so on, which are suitable forindustrial production.

In a third aspect, provided herein is a compound of Formula (V),

wherein:

R₁ is phenyl, methoxy, hydroxy, chloro, bromo, iodo, mesylate, triflateor 4-methylbenzenesulfonate;

R₂ is

and when R₁ is phenyl, R₂ is not

R₃ is H, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl; and

R₄ is H, —(C₁-C₄)alkyl, —(C₃-C₆)heterocyclyl, —(C₁-C₄)alkyl-aryl,trimethylsilyl, triethylsilyl or t-butyldimethylsilyl.

In some embodiments, R₁ is phenyl. In certain embodiments, R₃ is H,methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, benzyl oroptionally substituted benzyl. In some embodiments, R₄ is H, methyl,ethyl, n-propyl, i-propyl, n-butyl, t-butyl, trimethylsilyl,triethylsilyl, t-butyldimethylsilyl, triphenylmethyl, tetrahydrofuryl,benzyl or optionally substituted benzyl. In certain embodiments, R₂ is—COOH, —COOCH₃, —COOCH₂CH₃, —COOCH(CH₃)₂, —COOC(CH₃)₃, —COOCH₂Ph,—CH₂OH, —CH₂OCH₃, —CH₂OCH₂CH₃, —CH₂OCH(CH₃)₂, —CH₂OC(CH₃)₃, —CH₂OCH₂Ph,—CH₂OC(Ph)₃, —CH₂OSi(CH₃)₃, —CH₂OSi(CH₂CH₃)₃, —CH₂OSi(CH₃)₂C(CH₃)₃,—CONH₂, —CONHCH₃, —CONHCH₂CH₃, —CONHCH(CH₃)₂, —CONHC(CH₃)₃, —CONHCH₂Phor

and when R₁ is phenyl, R₂ is —CH₂OH, —CH₂OCH₃, —CH₂OCH₂CH₃,—CH₂OCH(CH₃)₂, —CH₂OC(CH₃)₃, —CH₂OCH₂Ph, —CH₂OC(Ph)₃, —CH₂OSi(CH₃)₃,—CH₂OSi(CH₂CH₃)₃, —CH₂OSi(CH₃)₂C(CH₃)₃, —CONH₂, —CONHCH₃, —CONHCH₂CH₃,—CONHCH(CH₃)₂, —CONHC(CH₃)₃, —CONHCH₂Ph or

In a fourth aspect, provided herein is a method of preparing a compoundof Formula (V):

wherein the compound of Formula (V) is prepared by a deprotectionreaction of a compound of Formula (IV):

in the presence of a base or an acid, wherein:

R₁ is phenyl, methoxy, hydroxy, chloro, bromo, iodo, mesylate, triflateor 4-methylbenzenesulfonate;

R₂ is

and when R₁ is phenyl, R₂ is not

R₃ is H, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl;

R₄ is H, —(C₁-C₄)alkyl, —(C₃-C₆)heterocyclyl, —(C₁-C₄)alkyl-aryl,trimethylsilyl, triethylsilyl or t-butyldimethylsilyl; and

R₅ is H, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl.

In some embodiments, the compound of Formula (IV) is prepared by asubstitution reaction of a compound of Formula (II) with a compound ofFormula (III) in the presence of a base;

In certain embodiments, the compound of Formula (II) is prepared by acondensation reaction of a compound of Formula (I);

wherein R₁ is as defined above; and

R₅ is H, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl.

In some embodiments, the compound of the Formula (IV) is prepared by aprocess comprising the following steps:

-   -   a) preparing a compound of Formula (II) by a condensation        reaction of a compound of Formula (I) in the presence of a base,

and

-   -   b) preparing a compound of Formula (IV) by a substitution        reaction of the compound of Formula (II) with a compound of        Formula (III) in the presence of a strong base;

-   -   wherein R₁ is phenyl;    -   R₂ is

-   -   R₃ is H, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl or        benzyl;    -   R₄ is H, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl,        benzyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl,        triphenylmethyl, tetrahydrofuryl;    -   R₅ is H, methyl, ethyl, n-propyl, i-propyl, n-butyl or benzyl;        and    -   R₆ is triflate, mesylate or 4-methylbenzenesulfonate.

In certain embodiments, the compound of Formula (II) is prepared by acondensation reaction of the compound of Formula (I) withN,N′-carbonyldiimidazole and a compound of Formula (VIII):

in the presence of magnesium chloride and triethylamine, wherein R₅ isH, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl.

In some embodiments, the compound of Formula (II) is prepared by acondensation reaction of the compound of Formula (I) with Meldrum'sacid, 4-dimethylaminopyridine, R₅OH and pivaloyl chloride in thepresence of N,N-diisopropylethylamine, R₅ is H, —(C₁-C₄)alkyl or—(C₁-C₄)alkyl-aryl.

In a fifth aspect, provided herein is a method of preparing sacubitril,

-   -   comprising the following steps:    -   a) preparing a compound of Formula (VI) by an enzymic catalytic        reaction of a compound of Formula (V) in the presence of        ω-transaminase and phosphopyridoxal,

-   -   b) optionally, preparing a compound of Formula (VII) from the        compound of Formula (VI):

and

-   -   c) preparing sacubitril from the compound of Formula (VII),        wherein:    -   R₁ is phenyl, methoxy, hydroxy, chloro, bromo, iodo, mesylate,        triflate or 4-methylbenzenesulfonate;    -   R₂ is

-   -   R₃ is H, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl; and    -   R₄ is H, —(C₁-C₄)alkyl, —(C₃-C₆)heterocyclyl,        —(C₁-C₄)alkyl-aryl, trimethylsilyl, triethylsilyl or        t-butyldimethylsilyl.

In certain embodiments, R₁ is phenyl; R₂ is

and R₃ is methyl, ethyl, propyl, i-propyl, n-butyl, t-butyl, benzyl oroptionally substituted benzyl.

In some embodiments, the method of preparing sacubitril comprises thefollowing steps:

a) preparing a compound of Formula (VII) by an enzymic catalyticreaction of a compound of Formula (V):

in the presence of ω-transaminase and phosphopyridoxal; and

b) preparing sacubitril by an amide condensation reaction of thecompound of Formula (VII) with succinic anhydride,

wherein R₁ is phenyl, and R₂ is

and R₃ is ethyl.

In certain embodiments, the compound of Formula (VII) is prepared by ahydrolysis reaction of the compound of Formula (VI) and then anesterification reaction of the hydrolysis product with ethanol.

In some embodiments, the compound of the Formula (VII) is prepared by aprocess comprising the following steps:

a) preparing a compound of Formula (X) by a reaction of a compound ofFormula (V) with a compound of Formula (IX),

b) preparing a compound of Formula (XI) from the compound of Formula(X),

c) preparing a compound of Formula (XII) from the compound of Formula(XI),

and

d) preparing a compound of Formula (VII) from the compound of Formula(XII),

wherein:

-   -   R₁ is phenyl, methoxy, hydroxy, chloro, bromo, iodo, mesylate,        triflate or 4-methylbenzenesulfonate;    -   R₂ is

-   -   R₃ is H, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl; and    -   R₇ is phenyl, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl.

In certain embodiments, the compound of Formula (IX) in step a) isD-phenylglycinol.

In some embodiments, the compound of Formula (XI) is prepared from thecompound of Formula (X) in the presence of titanium tetrachloride andtriethyl silicane in step b).

In certain embodiments, the compound of Formula (XII) is prepared fromthe compound of Formula (XI) in the presence of palladium-carbon in stepc).

In some embodiments, the compound of Formula (VII) is prepared from thecompound of Formula (XII) in ethanol in the presence of an acid in stepd).

In certain embodiments, the compound of the Formula (VII) is prepared bya process comprising the following steps:

a) preparing a compound of Formula (XIII) by a reaction of(R)-5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoic acid withD-phenylglycinol,

b) preparing a compound of Formula (XIV) from the compound of Formula(XIII) in the presence of titanium tetrachloride and triethyl silicane,

c) preparing a compound of Formula (XII) from the compound of Formula(XIV) in the presence of palladium-carbon,

and

d) preparing a compound of Formula (VII) by a ring opening reaction ofthe compound of Formula (XII):

DEFINITION OF TERMS

The invention is intended to cover all alternatives, modifications, andequivalents which are included within the scope of the present inventionas defined by the claims. One skilled in the art will recognize manymethods and materials similar or equivalent to those described herein,which could be used in the practice of the present invention. Thepresent invention is in no way limited to the methods and materialsdescribed herein. In the event that one or more of the incorporatedliterature, patents, and similar materials differs from or contradictsthis application, including but not limited to defined terms, termusage, described techniques, or the like, this application controls.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one skilled in theart to which this invention belongs. All patents and publicationsreferred to herein are incorporated by reference in their entirety.

As used herein, the following definitions shall be applied unlessotherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, and the Handbook of Chemistry and Physics, 75thEd. 1994. The term “comprising” or “comprise” is meant to be open ended,including the indicated component but not excluding other elements.

At various places in the present specification, substituents ofcompounds disclosed herein are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “—C₁-C₆ alkyl” is specifically intended toindividually disclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, andC₆ alkyl.

At various places in the present specification, linking substituents aredescribed. Where the structure clearly requires a linking group, theMarkush variables listed for that group are understood to be linkinggroups. For example, if the structure requires a linking group and theMarkush group definition for that variable lists “alkyl” or “aryl” thenit is understood that the “alkyl” or “aryl” represents a linkingalkylene group or arylene group, respectively.

The term “alkyl” refers to a saturated linear or branched-chainmonovalent hydrocarbon group of 1-20 carbon atoms, wherein the alkylgroup is optionally substituted with one or more substituents describedherein.

The term “heterocyclyl” refers to a saturated or partially unsaturated,monocyclic, bicyclic or tricyclic ring containing 3 to 12 ring atoms, inwhich at least one ring member is selected from nitrogen, sulfur andoxygen. Unless otherwise specified, the heterocyclyl group may be carbonor nitrogen linked, and a —CH₂— group can be optionally replaced by a—C(O)— group. In which, the sulfur can be optionally oxygenized toS-oxide and the nitrogen can be optionally oxygenized to N-oxide. Somenon-limiting examples of the heterocyclyl group include oxiranyl,azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl,3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl,1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl,2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl,homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, indolinyl, 1,2,3,4-tetrahydroisoquinolyl,1,3-benzodioxolyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and the like.Some non-limiting examples of heterocyclyl wherein —CH₂— group isreplaced by —C(O)— moiety include 2-oxopyrrolidinyl,oxo-1,3-thiazolidinyl, 2-piperidinonyl, 3,5-dioxopiperidinyl,pyrimidinedione-yl, and the like. Some non-limiting examples ofheterocyclyl wherein the ring sulfur atom is oxidized is sulfolanyl,1,1-dioxo-thiomorpholinyl. The heterocyclyl group may be optionallysubstituted with one or more substituents disclosed herein.

In some embodiments, heterocyclyl may be 6 membered heterocyclyl, whichrefers to a saturated or partially unsaturated monocyclic ringcontaining 6 ring atoms, of which at least one ring atom is selectedfrom nitrogen, sulfur and oxygen. Unless otherwise specified, theheterocyclyl group containing 6 ring atoms may be carbon or nitrogenlinked, and a —CH₂— group can be optionally replaced by a —C(O)— group.In which, the sulfur can be optionally oxygenized to S-oxide and thenitrogen can be optionally oxygenized to N-oxide. Examples of theheterocyclyl group containing 6 ring atoms include, but are not limitedto, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, dioxanyl, dithianyl and thioxanyl. Some non-limitingexamples of heterocyclyl wherein —CH₂— group is replaced by —C(O)—moiety include 2-piperidinonyl, 3,5-dioxopiperidinyl andpyrimidinedionyl. Some non-limiting examples of heterocyclyl wherein thering sulfur atom is oxidized is 1,1-dioxo-thiomorpholinyl. Theheterocyclyl group containing 6 ring atoms may be optionally substitutedwith one or more substituents disclosed herein.

The term “unsaturated” refers to a moiety having one or more units ofunsaturation.

The term “heteroatom” refers to one or more of oxygen, sulfur, nitrogen,phosphorus and silicon, including any oxidized form of nitrogen, sulfur,or phosphorus; primary, secondary, tertiary amine and the quaternizedform of any basic nitrogen; or a substitutable nitrogen of aheterocyclic ring, for example, N (as in 3,4-dihydro-2H-pyrrolyl), NH(as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl).

The term “aryl refers to monocyclic, bicyclic and tricyclic carbocyclicring systems having a total of six to fourteen ring members, or six totwelve ring members, or six to ten ring members, wherein at least onering in the system is aromatic, wherein each ring in the system contains3 to 7 ring members and that has a single point or multipoint ofattachment to the rest of the molecule. The term “aryl” and “aromaticring” can be used interchangeably herein. Examples of aryl ring mayinclude phenyl, naphthyl and anthracene. The aryl group may beoptionally and independently substituted with one or more substituentsdisclosed herein.

Mesylate (—OMs) disclosed herein is

triflate (—OTf) disclosed herein is

4-methylbenzenesulfonate (—OTs) is

and Ph is phenyl.

DETAILED DESCRIPTION OF THE INVENTION

In first aspect, provided herein are an intermediate for preparingsacubitril shown as a compound of Formula (V); and also a preparationmethod of the compound of Formula (V).

Provided herein is an intermediate for preparing sacubitril, shown as acompound of Formula (V):

wherein

R₁ may be phenyl, methoxy, hydroxy, chloro, bromo, iodo, mesylate(—OMs), triflate (—OTf) or 4-methylbenzenesulfonate (—OTs) and in someembodiments, R₁ is phenyl;

R₂ may be

R₃ may be H, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl; wherein —(C₁-C₄)alkylin some embodiments may be methyl, ethyl, n-propyl, i-propyl, n-butyl,t-butyl; wherein —(C₁-C₄)alkyl-aryl in some embodiments may be benzyl oroptionally substituted benzyl;

R₄ may be H, —(C₁-C₄)alkyl, —(C₃-C₆)heterocyclyl, —(C₁-C₄)alkyl-aryl,trimethylsilyl, triethylsilyl or t-butyldimethylsilyl; wherein—(C₁-C₄)alkyl in some embodiments may be methyl, ethyl, n-propyl,i-propyl, n-butyl, t-butyl; wherein —(C₁-C₄)alkyl-aryl in someembodiments may be benzyl or optionally substituted benzyl.

In some embodiments, when R₁ of any formulae disclosed herein is phenyl,R₂ is not

In some embodiments, the compound of Formula (V) disclosed herein,wherein R₂ is —COOH, —COOCH₃, —COOCH₂CH₃, —COOCH(CH₃)₂, —COOC(CH₃)₃,—COOCH₂Ph, —CH₂OH, —CH₂OCH₃, —CH₂OCH₂CH₃, —CH₂OCH(CH₃)₂, —CH₂OC(CH₃)₃,—CH₂OCH₂Ph, —CH₂OC(Ph)₃, —CH₂OSi(CH₃)₃, —CH₂OSi(CH₂CH₃)₃,—CH₂OSi(CH₃)₂C(CH₃)₃, —CONH₂, —CONHCH₃, —CONHCH₂CH₃, —CONHCH(CH₃)₂,—CONHC(CH₃)₃, —CONHCH₂Ph or

In some embodiments, the compound of Formula (V) may be one of thefollowing structures:

No. Compound of Formula (V) (1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

(13)

(14)

(15)

(16)

(17)

(18)

(19)

(20)

(21)

(22)

(23)

The compound of Formula (V) disclosed herein may be prepared by adeprotection reaction of a compound of Formula (IV):

wherein

R₁ may be phenyl, methoxy, hydroxy, chloro, bromo, iodo, mesylate(—OMs), triflate (—OTf) or 4-methylbenzenesulfonate (—OTs) and in someembodiments, R₁ is phenyl;

R₂ may be

In some embodiments, R₂ is

R₃ may be H, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl; wherein —(C₁-C₄)alkylin some embodiments may be methyl, ethyl, n-propyl, i-propyl, n-butyl,t-butyl; wherein —(C₁-C₄)alkyl-aryl in some embodiments may be benzyl oroptionally substituted benzyl;

R₄ may be H, —(C₁-C₄)alkyl, —(C₃-C₆)heterocyclyl, —(C₁-C₄)alkyl-aryl,trimethylsilyl, triethylsilyl or t-butyldimethylsilyl; wherein—(C₁-C₄)alkyl in some embodiments may be methyl, ethyl, n-propyl,i-propyl, n-butyl, t-butyl; wherein —(C₁-C₄)alkyl-aryl in someembodiments may be benzyl or optionally substituted benzyl;

R₅ may be H, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl; wherein —(C₁-C₄)alkylin some embodiments may be methyl, ethyl, n-propyl, i-propyl, n-butyl,t-butyl; wherein —(C₁-C₄)alkyl-aryl in some embodiments may be benzyl oroptionally substituted benzyl.

In some embodiments, the compound of Formula (V) is prepared by adeprotection reaction of the compound of Formula (IV) in the presence ofa base or an acid. In certain embodiments, the acid is trifluoroaceticacid. In some embodiments, the base is lithium hydroxide.

The compound of Formula (IV) disclosed herein may be prepared by asubstitution reaction of a compound of Formula (II) with a compound ofFormula (III):

wherein

R₁, R₂ and R₅ may be the groups as defined above;

R₆ may be triflate (—OTf), mesylate (—OMs) or 4-methylbenzenesulfonate(—OTs).

Chiral methyl may be introduced by a substitution reaction of thecompound of Formula (II) with the compound of Formula (III), and thusthe compound of Formula (IV) can be obtained. In some embodiments, thesubstitution reaction is carried out in the presence of a strong base;In some embodiments, the strong base is sodium hydride.

The compound of Formula (II) may be prepared by a condensation reactionof a compound of Formula (I):

wherein R₁ may be the groups as defined above.

In some embodiments, wherein the compound of Formula (II) is prepared bya condensation reaction of the compound of Formula (I) withN,N′-carbonyldiimidazole and a compound of Formula (VIII):

in the presence of magnesium chloride and triethylamine, wherein R₅ maybe the groups as defined above.

In some embodiments, the compound of Formula (II) is prepared by acondensation reaction of the compound of Formula (I) with Meldrum'sacid, 4-dimethylaminopyridine, R₅OH and pivaloyl chloride in thepresence of N,N-diisopropylethylamine, wherein R₅ may be the groups asdefined above.

In some embodiments, the method of preparing a compound of Formula (V)disclosed herein comprises the following steps:

wherein R₁ is phenyl;

R₂ is

wherein R₃ may be H, methyl, ethyl, propyl, i-propyl, n-butyl, t-butylor benzyl, and wherein R₄ is H, methyl, ethyl, propyl, i-propyl,n-butyl, t-butyl, benzyl, trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, triphenylmethyl, tetrahydropyranyl;

a) preparing a compound of Formula (II) by a condensation reaction of acompound of Formula (I) in the presence of a base;

wherein:

R₁ is phenyl;

R₅ is H, methyl, ethyl, n-propyl, i-propyl, n-butyl or benzyl;

b) preparing a compound of Formula (IV) by a substitution reaction ofthe compound of Formula (II) with a compound of Formula (III) in thepresence of a strong base;

wherein

R₁ is phenyl;

R₂ is

wherein R₃ may be H, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butylor benzyl, and wherein R₄ is H, methyl, ethyl, n-propyl, i-propyl,n-butyl, t-butyl, benzyl, trimethylsilyl, triethylsilyl ort-butyldimethylsilyl;

R₅ may be H, methyl, ethyl, propyl, i-propyl, n-butyl or benzyl;

R₆ may be triflate (—OTf), mesylate (—OMs) or 4-methylbenzenesulfonate(—OTs);

c) preparing the compound of Formula (V) by a deprotection reaction ofthe compound of Formula (IV) in the presence of a base or an acid.

The synthetic route of preparing the compound of Formula (V) disclosedherein is depicted as follows:

Under the inventive concept of the invention, those skilled in the artcan adjust the reaction conditions appropriately, such as selectingother suitable reaction solvents, adjusting the reaction temperature,and prolonging the reaction time to obtain better reaction results andso on according to the present disclosure based on the method forpreparing the compound of Formula (V) or an intermediate thereofdisclosed herein. The compound of Formula (V) can be obtained by theabove preparation method.

In second aspect, provided herein also are two methods for preparingsacubitril.

The first method of preparing sacubitril from the compound of Formula(V) may be depicted in the following scheme:

The first method of preparing sacubitril may comprise the followingsteps:

preparing the compound of Formula (VI) by a enzymic catalytic reactionof a compound of Formula (V):

wherein

R₁ is phenyl, methoxy, hydroxy, chloro, bromo, iodo, mesylate, triflateor 4-methylbenzenesulfonate;

R₂ is

R₃ is H, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl;

R₄ is H, —(C₁-C₄)alkyl, —(C₃-C₆)heterocyclyl, —(C₁-C₄)alkyl-aryl,trimethylsilyl, triethylsilyl or t-butyldimethylsilyl.

The first method of preparing sacubitril may comprise the followingsteps:

a) preparing a compound of Formula (VI) by an enzymic catalytic reactionof a compound of Formula (V),

wherein

R₁ may be phenyl, methoxy, hydroxy, chloro, bromo, iodo, mesylate(—OMs), triflate (—OTf) or 4-methylbenzenesulfonate (—OTs);

R₂ may be

R₃ may be H, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl; wherein —(C₁-C₄)alkylin some embodiments may be methyl, ethyl, n-propyl, i-propyl, n-butyl,t-butyl; wherein —(C₁-C₄)alkyl-aryl in some embodiments may be benzyl oroptionally substituted benzyl;

R₄ may be H, —(C₁-C₄)alkyl, —(C₃-C₆)heterocyclyl, —(C₁-C₄)alkyl-aryl,trimethylsilyl, triethylsilyl or t-butyldimethylsilyl; wherein—(C₁-C₄)alkyl in some embodiments may be methyl, ethyl, n-propyl,i-propyl, n-butyl, t-butyl; wherein —(C₁-C₄)alkyl-aryl in someembodiments may be benzyl or optionally substituted benzyl;

b) optionally, preparing a compound of Formula (VII) from the compoundof Formula (VI),

c) preparing sacubitril from the compound of Formula (VII).

In some embodiments, the first method of preparing sacubitril maycomprise the following steps:

a) preparing a compound of Formula (VI) by an enzymic catalytic reactionof a compound of Formula (V),

wherein R₁ is phenyl,

R₂ is

R₃ is H, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl; wherein —(C₁-C₄)alkyl insome embodiments may be methyl, ethyl, n-propyl, i-propyl, n-butyl,t-butyl; wherein —(C₁-C₄)alkyl-aryl in some embodiments may be benzyl oroptionally substituted benzyl;

b) optionally, preparing a compound of Formula (VII) from the compoundof Formula (VI),

c) preparing sacubitril from the compound of Formula (VII).

In some embodiments, the first method of preparing sacubitril maycomprise the following steps:

a) preparing a compound of Formula (VII) by an enzymic catalyticreaction of a compound of Formula (V),

wherein R₁ is phenyl,

wherein R₂ is

R₃ is ethyl;

b) preparing sacubitril by an amide condensation reaction of thecompound of Formula (VII) with succinic anhydride.

In some embodiments, in the above preparation method of sacubitril,wherein the enzymic catalytic reaction is carried out in the presence ofω-transaminase and phosphopyridoxal.

In some embodiments, in the above preparation method of sacubitril,wherein the compound of Formula (VII) may be prepared by a hydrolysisreaction of the compound of Formula (VI) and then an esterificationreaction of the hydrolysis product with ethanol.

The second method of preparing sacubitril from the compound of Formula(V) may be depicted in the following scheme:

The second method of preparing sacubitril may comprise the followingsteps:

preparing a compound of Formula (X) by a reaction of a compound ofFormula (V) with a compound of Formula (IX),

wherein

R₁ is phenyl, methoxy, hydroxy, chloro, bromo, iodo, mesylate, triflateor 4-methylbenzenesulfonate;

R₂ is

R₃ is H, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl,

R₇ is phenyl, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl.

The second method of preparing sacubitril may comprise the followingsteps:

preparing a compound of Formula (XI) from the compound of Formula (X):

wherein

R₁ is phenyl, methoxy, hydroxy, chloro, bromo, iodo, mesylate, triflateor 4-methylbenzenesulfonate; and

R₇ is phenyl, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl.

The second method of preparing sacubitril may comprise the followingsteps:

a) preparing a compound of Formula (X) by a reaction of a compound ofFormula (V) with a compound of Formula (IX),

wherein

R₁ may be phenyl, methoxy, hydroxy, chloro, bromo, iodo, mesylate(—OMs), triflate (—OTf) or 4-methylbenzenesulfonate (—OTs);

R₂ may be

R₃ may be H, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl; wherein —(C₁-C₄)alkylin some embodiments may be methyl, ethyl, n-propyl, i-propyl, n-butyl,t-butyl; wherein —(C₁-C₄)alkyl-aryl in some embodiments may be benzyl oroptionally substituted benzyl;

R₇ may be phenyl, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl; wherein—(C₁-C₄)alkyl in some embodiments may be methyl, ethyl, n-propyl,i-propyl, n-butyl, t-butyl; wherein —(C₁-C₄)alkyl-aryl in someembodiments may be benzyl or optionally substituted benzyl;

b) preparing a compound of Formula (XI) from the compound of Formula(X):

R₁ and R₇ are as defined in step a);

c) preparing a compound of Formula (XII) from the compound of Formula(XI):

d) preparing a compound of Formula (VII) from the compound of Formula(XII):

and

e) preparing sacubitril from the compound of Formula (VII).

In some embodiments, the compound of Formula (IX) is D-phenylglycinol.

In some embodiments, the compound of Formula (XI) is prepared from thecompound of Formula (X) in the presence of titanium tetrachloride andtriethyl silicane.

In some embodiments, the compound of Formula (XII) is prepared from thecompound of Formula (XI) in the presence of palladium on carbon (Pd/C).

In some embodiments, the compound of Formula (VII) is prepared from thecompound of Formula (XII) in ethanol in the presence of an acid. In someembodiments, the acid is hydrochloric acid.

In some embodiments, the second method of preparing sacubitril comprisesthe following steps:

a) preparing a compound of Formula (XIII) by a reaction of(R)-5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoic acid withD-phenylglycinol (as mentioned above compound (1)),

b) preparing a compound of Formula (XIV) from the compound of Formula(XIII) in the presence of titanium tetrachloride and triethyl silicane,

c) preparing a compound of Formula (XII) from the compound of Formula(XIV) using palladium on carbon (Pd/C) as a catalyst,

d) preparing a compound of Formula (VII) by a ring opening reaction ofthe compound of Formula (XII):

and

e) preparing sacubitril from the compound of Formula (VII);

The reaction route is shown as follows:

In the method of preparing sacubitril disclosed herein, sacubitril wasprepared by an amide condensation reaction of ((2R,4S)-ethyl5-([1,1′-biphenyl]-4-yl)-4-amino-2-methylpentanoate) represented by thecompound of Formula (VII) with butanedioic anhydride in the presence ofa base; the step was disclosed in prior art, such as in both WO2008031567 A1 and CN 104557600 A, it is known to the persons skilled inthe art.

The technology provided herein compared with prior art has advantages asfollows:

It provides a completely new sacubitril intermediate (V) and apreparation method thereof, the intermediate was prepared by using a lowcost readily available raw material biphenyl acetic acid, and sufferingfrom three steps of condensation, substitution, deprotection to getintermediate (V), each step has a high yield and simple operation; theintermediate has a similar parent structure as sacubitril, at present,no similar structures as this have been reported, and no methods ofpreparing sacubitril using a similar structure as an intermediate havebeen reported;

It provides a method of preparing sacubitril using intermediate (V) asthe raw material and enzyme catalyzed reaction as a key step; In thisroute, a chiral amino was introduced with high yield and highstereoselectivity in one step under enzymatic catalysis, the reactionconditions were mild, the shortest route can give sacubitril within twosteps; The introduction method of the chiral amino group in the priorart generally requires a chiral raw material, a chiral inductionreagent, a chiral catalyst or a chiral separation, and has somedisadvantages of high cost, unfriendly environment, low yield, poorstereoselectivity, long route and need of repeated protection anddeprotection, and other issues;

It provides a method of preparing sacubitril using intermediate (V) asthe raw material and chiral substituted glycinol as the chiralauxiliary, comprising steps of cyclization, deprotection, ring openingand amidation, the method compared with the prior method, the chiralauxiliary was replaced by (S)-1-(α-aminobenzyl)-2-naphthol tosubstituted glycine, which is cheaper and more readily available, thepreparation method of the raw material intermediate (V) is simple, andthe reaction conditions in each step are mild and simple, and aresuitable for industrial production.

EXAMPLES

In order to make persons skilled in the art understand the technicalsolutions of the present invention better, the present inventionexemplarily provides a part of the preparation examples, the presentinvention will be explained in more detail below by using non-limitingexamples.

The reagents used in the present invention are all commerciallyavailable or can be prepared by the methods described herein.

mL milliliter, g gram, h hour(s), N mol/L, 1H NMR H nuclear magneticspectrometer, MS mass spectrometry, HPLC high Performance LiquidChromatography, CDCl₃ deuterochloroform, DMSO-d₆ deuterated dimethylsulfoxide.

Intermediate (V) and Preparation Method Thereof

Example 1. Preparation of(R)-5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoic acid Example 1-a:Preparation of ethyl 4-([1,1′-biphenyl]-4-yl)-3-oxobutyrate

To a 500 mL three neck flask A were added 200 mL of ethyl acetate and28.64 g of N,N′-carbonyldiimidazole at room temperature, and then 25.00g of 4-biphenyl acetic acid was added in portions to flask A, thegeneration rate of gas was controlled. After the addition, the reactionliquid was heated to 45° C. and reacted for 3 hours, and then cooled to20 to 30° C., the flask was evacuated for pressure reduction for 1 hour,and ready for use. To a 1 L flask B were added 280 mL of ethyl acetate,28.06 g of ethyl potassium malonate (EtO₂CCH₂COOK) and 15.70 g ofmagnesium chloride (MgCl₂) at room temperature, the temperature wascontrolled at 20° C. to 30° C., and then 19.07 g of triethylamine (TEA)was added dropwise slowly. After the addition, the mixture was furtherstirred for 1 hour. To flask B was added the materials in flask A atroom temperature, the mixture was heated to 45° C. and reacted for 16hours. The reaction liquid was cooled to 20° C. to 30° C., and 180 mL of4 N hydrochloric acid solution was added, and the mixture waspartitioned, the organic layer was washed three times with 250 mL of6.5% sodium bicarbonate aqueous solution each time, the organic layerswere combined, the solvent was then stripped off in vacuo at 45° C. togive a yellow brown oil. To the obtained oil was added 150 mL ofn-hexane, the mixture was stirred at 20° C. to 30° C. for 18 hours andfiltered, the filter cake was washed with n-hexane and dried at 40° C.to 50° C. in vacuo for 5 hours to give ethyl4-([1,1′-biphenyl]-4-yl)-3-oxobutyrate 26.3 g, the yield is 79.1%. ¹HNMR (600 MHz, CDCl₃) δ 7.60 (dt, J=15.9, 6.1 Hz, 4H), 7.47 (t, J=7.7 Hz,2H), 7.37 (dt, J=9.7, 7.9 Hz, 1H), 7.33-7.28 (m, 2H), 4.25-4.18 (m, 2H),3.90 (s, 2H), 3.52 (s, 2H), 1.30 (t, J=7.1 Hz, 3H). ESI-MS (m/z): 283.3([M+H]+).

Example 1-b: Preparation of (3R)-1-ethyl-4-methyl2-(2-([1,1′-biphenyl]-4-yl)acetyl)-3-methylsuccinate

To a 500 mL flask were added 5.31 g of sodium hydride (NaH) and 100 mLdried tetrahydrofuran (THF), the flask was degassed and filled withnitrogen 3 times. The reaction liquid was cooled to 0° C., a solution of25.00 g of ethyl 4-([1,1′-biphenyl]-4-yl)-3-oxobutyrate in 100 mL oftetrahydrofuran (THF) was added dropwise slowly under nitrogen. Afterthe addition, the reaction liquid was heated to 20° C. to 30° C. andstirred for additional 30 min. The reaction liquid was cooled to 0° C.,and a solution of (R)-methyl-2-(4-methylbenzenesulfonate)propionate(31.37 g) in tetrahydrofuran (THF) (100 mL) was added dropwise slowly,after the addition, the reaction liquid was heated to 20° C. to 30° C.and stirred for 1.5 hours. After the raw materials were consumedcompletely monitored by HPLC, to the reaction liquid was added 150 mL of2 N hydrochloric acid to adjust pH to 2-3, and the reaction liquid wasextracted with ethyl acetate 3 times, each time with 100 mL. The organiclayers were combined and washed 2 times with 200 mL each time of water,and then concentrated to give an oil(3R)-1-ethyl-4-methyl2-(2-([1,1′-biphenyl]-4-yl)acetyl)-3-methylsuccinate48.60 g, which was used in the next step without further purification.

Example 1-c: Preparation of(R)-5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoic acid

To a 500 mL flask were added 13.04 g of (3R)-1-ethyl-4-methyl2-(2-([1,1′-biphenyl]-4-yl)acetyl)-3-methylsuccinate and 130 mL oftetrahydrofuran (THF), the reaction liquid was cooled to 0° C., asolution of 3.71 g of lithium hydroxide monohydrate (LiOH.H₂O) in 130 mLof water was added dropwise slowly. After the addition, the reactionliquid was heated to 60° C. to 70° C. and stirred for additional 16hours. After the raw materials were consumed completely monitored byHPLC, the reaction liquid was cooled to 20° C. to 30° C., 100 mL of 1 Nhydrochloric acid was added dropwise slowly to adjust pH to 2-3, and thereaction liquid was extracted with ethyl acetate 2 times, each time with100 mL. The organic layers were combined and concentrated to give an oil(R)-5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoic acid 8.50 g, theyield was 85.1%. ¹H NMR (600 MHz, DMSO-d₆) δ 12.16 (s, 1H), 7.66 (d,J=7.3 Hz, 2H), 7.61 (d, J=8.1 Hz, 2H), 7.46 (t, J=7.7 Hz, 2H), 7.36 (t,J=7.4 Hz, 1H), 7.28 (d, J=8.1 Hz, 2H), 3.82 (s, 2H), 2.88 (dd, J=17.7,8.1 Hz, 1H), 2.76-2.69 (m, 1H), 2.61 (dd, J=17.7, 5.4 Hz, 1H), 1.05 (dd,J=16.4, 7.1 Hz, 3H). ESI-MS (m/z): 283.3 ([M+H]+).

Example 2. Preparation of (R)-methyl5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoate Example 2-a:Preparation of t-butyl 4-([1,1′-biphenyl]-4-yl)-3-oxobutyrate

To a 500 mL flask were added 10.61 g of 4-biphenylacetic acid, 8.65 g ofMeldrum's acid, 0.61 g of 4-dimethylaminopyridine (DMAP) and 80 mL ofdimethylacetamide (DMAC) at room temperature in turn, the mixture wasstirred to dissolution. To the reaction liquid was added 13.57 g ofN,N-diisopropylethylamine (DIPEA) dropwise slowly, after the addition,6.63 g of pivaloyl chloride was added dropwise slowly and then themixture was heated to 50° C. and stirred for 20 hours. To the reactionliquid was added 18.5 g of t-butyl alcohol (t-BuOH), and the mixture washeated to 100° C. for 7 hours. After the raw materials were consumedcompletely monitored by HPLC, the reaction liquid was cooled to 20° C.to 30° C., 200 mL of water was added, and the reaction liquid wasextracted with ethyl acetate 3 times, each time with 100 mL. The organiclayers were combined and concentrated to give t-butyl4-([1,1′-biphenyl]-4-yl)-3-oxobutyrate 13.34 g, the yield was 86%. ¹HNMR (600 MHz, CDCl₃) δ 7.57 (t, J=6.8 Hz, 4H), 7.43 (t, J=7.4 Hz, 2H),7.38-7.32 (m, 1H), 7.31-7.25 (m, 2H), 3.87 (s, 2H), 3.41 (s, 2H), 1.47(s, 9H). ESI-MS (m/z): 311.4 ([M+H]+).

Example 2-b: Preparation of(3R)-1-t-butyl-4-methyl-2-(2-([1,1′-biphenyl]-4-yl)acetyl)-3-methylsuccinate

To a 500 mL flask were added 5.31 g of sodium hydride (NaH) and 100 mLdried tetrahydrofuran (THF), the flask was degassed and filled withnitrogen 3 times. The reaction liquid was cooled to 0° C., a solution of25.00 g of t-butyl 4-([1,1′-biphenyl]-4-yl)-3-oxobutyrate in 100 mL oftetrahydrofuran was added dropwise slowly under nitrogen. After theaddition, the reaction liquid was heated to 20° C. to 30° C. and stirredfor additional 30 min. The reaction liquid was cooled to 0° C., and asolution of 31.37 g of (R)-methyl-2-(triflate)propionate in 100 mL oftetrahydrofuran was added dropwise slowly, after the addition, thereaction liquid was heated to 20° C. to 30° C. and stirred for 1.5hours. After the raw materials were consumed completely monitored byHPLC, to the reaction liquid was added 150 mL of 2 N hydrochloric acidto adjust pH to 2-3, and the reaction liquid was extracted with ethylacetate 3 times, each time with 100 mL. The organic layers were combinedand washed 2 times with 200 mL each time of water, then concentrated togive an oil (3R)-1-t-butyl-4-methyl2-(-2-([1,1′-biphenyl]-4-yl)acetyl)-3-methylsuccinate 48.60 g, which wasused in the next step without further purification.

Example 2-c: Preparation of (R)-methyl5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoate

To a 100 mL flask were added 6.00 g of(3R)-1-t-butyl-4-methyl-2-(2-([1,1′-biphenyl]-4-yl)acetyl)-3-methylsuccinate,30 mL of dichloromethane (DCM) and 11.01 g of trifluoroacetic acid(CF₃COOH), the mixture was heated to 42° C. with stirring and reactedfor 22 hours. After the raw materials were consumed completely monitoredby HPLC, to the reaction liquid was added 150 mL of 6.5% sodiumbicarbonate solution dropwise slowly, and 150 mL of 2 N hydrochloricacid was added to adjust pH to 2-3, and the reaction liquid wasextracted with ethyl acetate 3 times, each time with 100 mL. The organiclayers were combined and washed 2 times with 200 mL each time of water,then concentrated to give an oil (R)-methyl5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoate 4.10 g, the yield was91.5%. ¹H NMR (400 MHz, CDCl₃) δ 7.60 (t, J=7.7 Hz, 4H), 7.46 (t, J=7.6Hz, 2H), 7.37 (t, J=7.3 Hz, 1H), 7.30 (d, J=8.1 Hz, 2H), 3.78 (s, 2H),3.69 (s, 3H), 3.04-2.94 (m, 2H), 2.60-2.51 (m, 1H), 1.18 (d, J=6.8 Hz,3H). ESI-MS (m/z): 297.3 ([M+H]+).

Example 3. Preparation of (R)-ethyl5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoate Example 3-a:Preparation of t-butyl 4-([1,1′-biphenyl]-4-yl)-3-oxobutyrate

The procedure is the same as the procedure of Example 2-a.

Example 3-b: Preparation of(3R)-1-t-butyl-4-ethyl-2-(2-([1,1′-biphenyl]-4-yl)acetyl)-3-methylsuccinate

To a 500 mL flask were added 5.31 g of sodium hydride (NaH) and 100 mLdried tetrahydrofuran (THF), the flask was degassed and filled withnitrogen 3 times. The reaction liquid was cooled to 0° C., a solution of25.00 g of t-butyl 4-([1,1′-biphenyl]-4-yl)-3-oxobutyrate in 100 mL oftetrahydrofuran was added dropwise slowly under nitrogen. After theaddition, the reaction liquid was heated to a temperature of 20° C. to30° C. and stirred for additional 30 min. The reaction liquid was cooledto 0° C., and a solution of 33.37 g of (R)-ethyl-2-(triflate)propionatein 100 mL of tetrahydrofuran was added dropwise slowly, after theaddition, the reaction liquid was heated to a temperature of 20° C. to30° C. and stirred for 1.5 hours. After the raw materials were consumedcompletely monitored by HPLC, to the reaction liquid was added 150 mL of2 N hydrochloric acid to adjust pH to 2-3, and the reaction liquid wasextracted with ethyl acetate 3 times, each time with 100 mL. The organiclayers were combined and washed 2 times with 200 mL each time of water,then concentrated to give an oil(3R)-1-t-butyl-4-ethyl2-(-2-([1,1′-biphenyl]-4-yl)acetyl)-3-methylsuccinate49.60 g, which was used in the next step without further purification.

Example 3-c: Preparation of (R)-ethyl5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoate

To a 100 mL flask were added 6.00 g of(3R)-1-t-butyl-4-ethyl-2-(2-([1,1′-biphenyl]-4-yl)acetyl)-3-methylsuccinate,30 mL of dichloromethane (DCM) and 11.01 g of trifluoroacetic acid(CF₃COOH), the mixture was heated to 42° C. with stirring and reactedfor 22 hours. After the raw materials were consumed completely monitoredby HPLC, to the reaction liquid was added 150 mL of 6.5% sodiumbicarbonate solution dropwise slowly, and 150 mL of 2 N hydrochloricacid was added to adjust pH to 2-3, and the reaction liquid wasextracted with ethyl acetate 3 times, each time with 100 mL. The organiclayers were combined and washed 2 times with 200 mL each time of water,then concentrated in vacuo to give an oil (R)-ethyl5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoate 4.17 g, the yield was92%. ¹H NMR (400 MHz, CDCl₃) δ 7.60 (t, J=7.7 Hz, 4H), 7.47 (t, J=7.7Hz, 2H), 7.37 (t, J=7.3 Hz, 1H), 7.30 (d, J=8.1 Hz, 2H), 4.06 (q, J=7.1Hz, 2H), 3.78 (s, 2H), 3.04-2.94 (m, 2H), 2.60-2.51 (m, 1H), 1.20-1.15(m, 6H). ESI-MS (m/z): 311.4 ([M+H]+).

Example 4. Preparation of(R)-isopropyl-benzyl-5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoateExample 4-a: Preparation of t-butyl4-([1,1′-biphenyl]-4-yl)-3-oxobutyrate

The procedure is the same as the procedure of Example 2-a.

Example 4-b: Preparation of(3R)-1-t-butyl-4-isopropyl-2-(2-([1,1′-biphenyl]-4-yl)acetyl)-3-methylsuccinate

To a 500 mL flask were added 5.31 g of sodium hydride (NaH) and 100 mLdried tetrahydrofuran (THF), the flask was degassed and filled withnitrogen 3 times. The reaction liquid was cooled to 0° C., a solution of25.00 g of t-butyl 4-([1,1′-biphenyl]-4-yl)-3-oxobutyrate in 100 mL oftetrahydrofuran was added dropwise slowly under nitrogen. After theaddition, the reaction liquid was heated to a temperature of 20° C. to30° C. and stirred for additional 30 min. The reaction liquid was cooledto 0° C., and a solution of 33.37 g of(R)-isopropyl-2-(triflate)propionate in 100 mL of tetrahydrofuran wasadded dropwise slowly, after the addition, the reaction liquid washeated to a temperature of 20° C. to 30° C. and stirred for 1.5 hours.After the raw materials were consumed completely monitored by HPLC, tothe reaction liquid was added 150 mL of 2 N hydrochloric acid to adjustpH to 2-3, and the reaction liquid was extracted with ethyl acetate 3times, each time with 100 mL. The organic layers were combined andwashed 2 times with 200 mL each time of water, then concentrated invacuo to give an oil(3R)-1-t-butyl-4-isopropyl-2-(-2-([1,1′-biphenyl]-4-yl)acetyl)-3-methylsuccinate50.60 g, which was used in the next step without further purification.

Example 4-c: Preparation of (R)-isopropylbenzyl-5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoate

To a 100 mL flask were added 6.00 g of(3R)-1-t-butyl-4-isopropyl-2-(2-([1,1′-biphenyl]-4-yl)acetyl)-3-methylsuccinate,30 mL of dichloromethane (DCM) and 11.01 g of trifluoroacetic acid(CF₃COOH), the mixture was heated to 42° C. with stirring and reactedfor 22 hours. After the raw materials were consumed completely monitoredby HPLC, to the reaction liquid was added 150 mL of 6.5% sodiumbicarbonate solution dropwise slowly, and 150 mL of 2 N hydrochloricacid was added to adjust pH to 2-3, and the reaction liquid wasextracted with ethyl acetate 3 times, each time with 100 mL. The organiclayers were combined and washed 2 times with 200 mL each time of water,then concentrated in vacuo to give an oil (R)-isopropyl5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoate 3.80 g, the yield was83.0%. ¹H NMR (600 MHz, CDCl₃) δ 7.60 (dt, J=15.9, 6.1 Hz, 4H), 7.47 (t,J=7.7 Hz, 2H), 7.37 (dt, J=9.7, 7.9 Hz, 1H), 7.33-7.28 (m, 2H), 4.93 (m,1H), 3.78 (s, 2H), 3.04-2.94 (m, 2H), 2.60-2.51 (m, 1H), 1.30 (d, J=7.1Hz, 6H), 1.18 (d, J=6.8 Hz, 3H). ESI-MS (m/z): 325.4 ([M+H]+).

Example 5. Preparation of(R)-benzyl-benzyl-5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoateExample 5-a: Preparation of t-butyl4-([1,1′-biphenyl]-4-yl)-3-oxobutyrate

To a 1 L flask were added 20.00 g of 4-biphenylacetic acid, 14.96 g ofMeldrum's acid, 0.61 g of 4-dimethylaminopyridine (DMAP), 21.40 g ofN,N-dicyclohexylcarbodiimide (DCC) and 200 mL of dichloromethane at roomtemperature in turn, the mixture was cooled to 0° C. and stirred for 12hours. The mixture was filtered to remove the precipitated solid, thefiltrate was concentrated to give a light-yellow oil. To the above oilwas added 95 mL of t-butanol, the mixture was heated to 82° C. undernitrogen. The raw materials were consumed monitored by TLC, the reactionliquid was distilled under reduced pressure to remove t-butanol, to theresidue was added 100 mL of dichloromethane, the resulting mixture waswashed with water and saturated sodium chloride aqueous solutionrespectively, the organic layers were combined and concentrated in vacuoto give t-butyl 4-([1,1′-biphenyl]-4-yl)-3-oxobutyrate 24.89 g, theyield was 85%. ¹H NMR (600 MHz, CDCl₃) δ 7.57 (t, J=6.8 Hz, 4H), 7.43(t, J=7.4 Hz, 2H), 7.38-7.32 (m, 1H), 7.31-7.25 (m, 2H), 3.87 (s, 2H),3.41 (s, 2H), 1.47 (s, 9H). ESI-MS (m/z): 311.4 ([M+H]+).

Example 5-b: Preparation of(3R)-4-benzyl-1-t-butyl-2-(2-([1,1′-biphenyl]-4-yl)acetyl)-3-methylsuccinate

To a 500 mL flask were added 5.31 g of sodium hydride (NaH) and 100 mLdried tetrahydrofuran (THF), the flask was degassed and filled withnitrogen 3 times. The reaction liquid was cooled to 0° C., a solution of25.00 g of t-butyl 4-([1,1′-biphenyl]-4-yl)-3-oxobutyrate in 100 mL oftetrahydrofuran was added dropwise slowly under nitrogen. After theaddition, the reaction liquid was heated to a temperature of 20° C. to30° C. and stirred for additional 30 min. The reaction liquid was cooledto 0° C., and a solution of 33.37 g of (R)-benzyl-2-(triflate)propionatein 100 mL of tetrahydrofuran was added dropwise slowly, after theaddition, the reaction liquid was heated to a temperature of 20° C. to30° C. and stirred for 1.5 hours. After the raw materials were consumedcompletely monitored by HPLC, to the reaction liquid was added 150 mL of2 N hydrochloric acid to adjust pH to 2-3, and the reaction liquid wasextracted with ethyl acetate 3 times, each time with 100 mL. The organiclayers were combined and washed 2 times with 200 mL each time of water,then concentrated in vacuo to give an oil(3R)-4-benzyl-1-t-butyl-2-(2-([1,1′-biphenyl]-4-yl)acetyl)-3-methylsuccinate50.60 g, which was used in the next step without further purification.

Example 5-c: Preparation of(R)-benzyl-benzyl-5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoate

To a 100 mL flask were added 6.00 g of(3R)-4-benzyl-1-t-butyl-2-(2-([1,1′-biphenyl]-4-yl)acetyl)-3-methylsuccinate,30 mL of dichloromethane (DCM) and 11.01 g of trifluoroacetic acid(CF₃COOH), the mixture was heated to 42° C. with stirring and reactedfor 22 hours. After the raw materials were consumed completely monitoredby HPLC, to the reaction liquid was added 150 mL of 6.5% sodiumbicarbonate solution dropwise slowly, and 150 mL of 2 N hydrochloricacid was added to adjust pH to 2-3, and the reaction liquid wasextracted with ethyl acetate 3 times, each time with 100 mL. The organiclayers were combined and washed 2 times with 200 mL each time of water,then concentrated in vacuo to give an oil (R)-benzyl5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoate 4.10 g, the yield was86.7%. ¹H NMR (400 MHz, CDCl₃) δ 7.60 (t, J=7.7 Hz, 4H), 7.46 (t, J=7.6Hz, 2H), 7.40-7.33 (m, 5H), 7.37 (t, J=7.3 Hz, 1H), 7.30 (d, J=8.1 Hz,2H), 5.22 (s, 2H), 3.78 (s, 2H), 3.04-2.94 (m, 2H), 2.60-2.51 (m, 1H),1.18 (d, J=6.8 Hz, 3H). ESI-MS (m/z): 373.5 ([M+H]+).

Example 6. Preparation of(R)-5-([1,1′-biphenyl]-4-yl)-N,2-dimethyl-4-oxovaleramide Example 6-a:Preparation of ethyl 4-([1,1′-biphenyl]-4-yl)-3-oxobutyrate

The procedure is the same as the procedure of Example 1-a.

Example 6-b: Preparation of(3R)-ethyl-2-(2-([1,1′-biphenyl]-4-yl)acetyl)-3-methyl-4-methylamino-4-oxobutyrate

To a 500 mL flask were added 5.31 g of sodium hydride (NaH) and 100 mLdried tetrahydrofuran (THF), the flask was degassed and filled withnitrogen 3 times. The reaction liquid was cooled to 0° C., a solution of25.00 g of ethyl 4-([1,1′-biphenyl]-4-yl)-3-oxobutyrate in 100 mL oftetrahydrofuran (THF) was added dropwise slowly under nitrogen. Afterthe addition, the reaction liquid was heated to a temperature of 20° C.to 30° C. and stirred for additional 30 min. The reaction liquid wascooled to 0° C., and a solution of 31.37 g of(R)-1-methylamino-1-oxopropyl-2-yl-4-methylbenzenesulfonate in 100 mL oftetrahydrofuran (THF) was added dropwise slowly, after the addition, thereaction liquid was heated to a temperature of 20° C. to 30° C. andstirred for 1.5 hours. After the raw materials were consumed completelymonitored by HPLC, to the reaction liquid was added 150 mL of 2 Nhydrochloric acid to adjust pH to 2-3, and the reaction liquid wasextracted with ethyl acetate 3 times, each time with 100 mL. The organiclayers were combined and washed 2 times with 200 mL each time of water,then concentrated in vacuo to give an oil (3R)-ethyl2-(2-([1,1′-biphenyl]-4-yl)acetyl)-3-methyl-4-methylamino-4-oxobutyrate48.60 g, which was used in the next step without further purification.

Example 6-c: Preparation of(R)-5-([1,1′-biphenyl]-4-yl)-N,2-dimethyl-4-oxovaleramide

To a 500 mL flask were added 15.00 g of(3R)-ethyl-2-(2-([1,1′-biphenyl]-4-yl)acetyl)-3-methyl-4-methylamino-4-oxobutyrateand 130 mL of tetrahydrofuran (THF), the reaction liquid was cooled to0° C., a solution of 4.00 g of lithium hydroxide monohydrate (LiOH.H₂O)in 130 mL of water was added dropwise slowly. After the addition, thereaction liquid was heated to a temperature of 60° C. to 70° C. andstirred for additional 16 hours. After the raw materials were consumedcompletely monitored by HPLC, the reaction liquid was cooled to atemperature of 20° C. to 30° C., 100 mL of 1 N hydrochloric acid wasadded to adjust pH to 2-3, and the reaction liquid was extracted withethyl acetate 3 times, each time with 100 mL. The organic layers werecombined and washed with water 2 times, each time with 200 mL, and thenconcentrated in vacuo to give an oil(R)-5-([1,1′-biphenyl]-4-yl)-N,2-dimethyl-4-oxovaleramide 10.43 g, theyield is 86.5%. ¹H NMR (600 MHz, DMSO-d₆) δ 12.16 (s, 1H), 7.66 (d,J=7.3 Hz, 2H), 7.61 (d, J=8.1 Hz, 2H), 7.46 (t, J=7.7 Hz, 2H), 7.36 (t,J=7.4 Hz, 1H), 7.28 (d, J=8.1 Hz, 2H), 3.82 (s, 2H), 3.05 (s, 3H), 2.88(dd, J=17.7, 8.1 Hz, 1H), 2.76-2.69 (m, 1H), 2.61 (dd, J=17.7, 5.4 Hz,1H), 1.05 (dd, J=16.4, 7.1 Hz, 3H). ESI-MS (m/z): 296.3 ([M+H]+).

Example 7. Preparation of(R)-5-([1,1′-biphenyl]-4-yl)-N-t-butyl-2-methyl-4-oxovaleramide Example7-a: Preparation of ethyl 4-([1,1′-biphenyl]-4-yl)-3-oxobutyrate

The procedure is the same as the procedure of Example 1-a.

Example 7-b: Preparation of(3R)-ethyl-2-(2-([1,1′-biphenyl]-4-yl)acetyl)-3-methyl-4-t-butylamino-4-oxobutyrate

To a 500 mL flask were added 5.31 g of sodium hydride (NaH) and 100 mLdried tetrahydrofuran (THF), the flask was degassed and filled withnitrogen 3 times. The reaction liquid was cooled to 0° C., a solution of25.00 g of ethyl 4-([1,1′-biphenyl]-4-yl)-3-oxobutyrate in 100 mL oftetrahydrofuran (THF) was added dropwise slowly under nitrogen. Afterthe addition, the reaction liquid was heated to a temperature of 20° C.to 30° C. and stirred for additional 30 min. The reaction liquid wascooled to 0° C., and a solution of 31.37 g of(R)-1-t-butylamino-1-oxopropyl-2-yl-4-methylbenzenesulfonate in 100 mLof tetrahydrofuran (THF) was added dropwise slowly, after the addition,the reaction liquid was heated to a temperature of 20° C. to 30° C. andstirred for 1.5 hours. After the raw materials were consumed completelymonitored by HPLC, to the reaction liquid was added 150 mL of 2 Nhydrochloric acid to adjust pH to 2-3, and the reaction liquid wasextracted with ethyl acetate 3 times, each time with 100 mL. The organiclayers were combined and washed with water 2 times, each time with 200mL, and then concentrated in vacuo to give an oil(3R)-ethyl-2-(2-([1,1′-biphenyl]-4-yl)acetyl)-3-methyl-4-t-butylamino-4-oxobutyrate48.60 g, which was used in the next step without further purification.

Example 7-c: Preparation of(R)-5-([1,1′-biphenyl]-4-yl)-N-t-butyl-2-methyl-4-oxovaleramide

To a 500 mL flask were added 15.00 g of(3R)-ethyl-2-(2-([1,1′-biphenyl]-4-yl)acetyl)-3-methyl-4-t-butylamino-4-oxobutyrateand 130 mL of tetrahydrofuran (THF), the reaction liquid was cooled to0° C., a solution of 4.00 g of lithium hydroxide monohydrate (LiOH.H₂O)in 130 mL of water was added dropwise slowly. After the addition, thereaction liquid was heated to a temperature of 60° C. to 70° C. andstirred for additional 16 hours. After the raw materials were consumedcompletely monitored by HPLC, the reaction liquid was cooled to atemperature of 20° C. to 30° C., 100 mL of 1 N hydrochloric acid wasadded to adjust pH to 2-3, and the reaction liquid was extracted withethyl acetate 3 times, each time with 100 mL. The organic layers werecombined and washed 2 times with 200 mL each time of water, thenconcentrated to give an oil(R)-5-([1,1′-biphenyl]-4-yl)-N-t-butyl-2-methyl-4-oxovaleramide 10.05 g,the yield was 81.3%. ¹H NMR (600 MHz, DMSO-d₆) δ 12.16 (s, 1H), 7.66 (d,J=7.3 Hz, 2H), 7.61 (d, J=8.1 Hz, 2H), 7.46 (t, J=7.7 Hz, 2H), 7.36 (t,J=7.4 Hz, 1H), 7.28 (d, J=8.1 Hz, 2H), 3.82 (s, 2H), 2.88 (dd, J=17.7,8.1 Hz, 1H), 2.76-2.69 (m, 1H), 2.61 (dd, J=17.7, 5.4 Hz, 1H), 1.39 (s,9H), 1.05 (dd, J=16.4, 7.1 Hz, 3H). ESI-MS (m/z): 338.4 ([M+H]+).

Example 8. Preparation of(R)-1-([1,1′-biphenyl]-4-yl)-4-methyl-5-(triphenylmethoxy)-2-pentanoneExample 8-a: Preparation of ethyl 4-([1,1′-biphenyl]-4-yl)-3-oxobutyrate

The procedure is the same as the procedure of Example 1-a.

Example 8-b: Preparation of ethyl4-([1,1′-biphenyl]-4-yl)-3-oxo-2-((R)-1-(triphenylmethoxy)propan-2-yl)-butyrate

To a 500 mL flask were added 5.31 g of sodium hydride (NaH) and 100 mLof dried toluene, the flask was degassed and filled with nitrogen 3times. The reaction liquid was cooled to 0° C., a solution of 25.00 g ofethyl 4-([1,1′-biphenyl]-4-yl)-3-oxobutyrate in 100 mL of toluene wasadded dropwise slowly under nitrogen. After the addition, the reactionliquid was heated to a temperature of 20° C. to 30° C. and stirred foradditional 30 min. The reaction liquid was cooled to 0° C., and asolution of 31.37 g of(R)-1-triphenylmethoxyprop-2-yl-4-methylbenzenesulfonate in 100 mL oftetrahydrofuran (THF) was added dropwise slowly, after the addition, thereaction liquid was heated to a temperature of 60° C. to 70° C. andstirred for 1.5 hours. After the raw materials were consumed completelymonitored by HPLC, to the reaction liquid was added 150 mL of 2 Nhydrochloric acid to adjust pH to 2-3, and the reaction liquid wasextracted with ethyl acetate 3 times, each time with 100 mL. The organiclayers were combined and washed with water 2 times, each time with 200mL, and then concentrated in vacuo to give an oil ethyl4-([1,1′-biphenyl]-4-yl)-3-oxo-2-((R)-1-(triphenylmethoxy)propan-2-yl)-butyrate46.60 g, which was used in the next step without further purification.

Example 8-c: Preparation of(R)-1-([1,1′-biphenyl]-4-yl)-4-methyl-5-(triphenylmethoxy)-2-pentanone

To a 500 mL flask were added 15.00 g of ethyl4-([1,1′-biphenyl]-4-yl)-3-oxo-2-((R)-1-(triphenylmethoxy)propan-2-yl)-butyrateand 130 mL of tetrahydrofuran (THF), the reaction liquid was cooled to0° C., a solution of 4.00 g of lithium hydroxide monohydrate (LiOH.H₂O)in 130 mL of water was added dropwise slowly. After the addition, thereaction liquid was heated to a temperature of 60° C. to 70° C. andstirred for additional 16 hours. After the raw materials were consumedcompletely monitored by HPLC, the reaction liquid was cooled to atemperature of 20° C. to 30° C., 100 mL of 1 N hydrochloric acid wasadded to adjust pH to 2-3, and the reaction liquid was extracted withethyl acetate 3 times, each time with 100 mL. The organic layers werecombined and washed with water 2 times, each time with 200 mL, and thenconcentrated in vacuo to give an oil(R)-1-([1,1′-biphenyl]-4-yl)-4-methyl-5-(triphenylmethoxy)-2-pentanone11.24 g, the yield was 85.6%. ¹H NMR (400 MHz, CDCl₃) δ 7.60 (t, J=7.7Hz, 4H), 7.46 (t, J=7.6 Hz, 2H), 7.40-7.33 (m, 5H), 7.38 (m, 15H), 7.37(t, J=7.3 Hz, 1H), 7.30 (d, J=8.1 Hz, 2H), 3.71 (s, 2H), 3.21 (d, J=6.8Hz, 2H), 3.04-2.94 (m, 2H), 2.60-2.51 (m, 1H), 1.18 (d, J=6.8 Hz, 3H).ESI-MS (m/z): 511.6 ([M+H]+).

Example 9. Preparation of(R)-1-([1,1′-biphenyl]-4-yl)-4-methyl-5-(triethylsilyloxy)-2-pentanoneExample 9-a: Preparation of ethyl 4-([1,1′-biphenyl]-4-yl)-3-oxobutyrate

The procedure is the same as the procedure of Example 1-a.

Example 9-b: Preparation of ethyl4-([1,1′-biphenyl]-4-yl)-3-oxo-2-((R)-1-(triethylsilyloxy)prop-2-yl)-butyrate

To a 500 mL flask were added 5.31 g of sodium hydride (NaH) and 100 mLof dried toluene, the flask was degassed and filled with nitrogen 3times. The reaction liquid was cooled to 0° C., a solution of 25.00 g ofethyl 4-([1,1′-biphenyl]-4-yl)-3-oxobutyrate in 100 mL of toluene wasadded dropwise slowly under nitrogen. After the addition, the reactionliquid was heated to a temperature of 20° C. to 30° C. and stirred foradditional 30 min. The reaction liquid was cooled to 0° C., and asolution of 31.37 g of(R)-1-triethylsilyloxyprop-2-yl-4-methylbenzenesulfonate in 100 mL oftoluene was added dropwise slowly, after the addition, the reactionliquid was heated to a temperature of 60° C. to 70° C. and stirred for1.5 hours. After the raw materials were consumed completely monitored byHPLC, to the reaction liquid was added 150 mL of 2 N hydrochloric acidto adjust pH to 2-3, and the reaction liquid was extracted with ethylacetate 3 times, each time with 100 mL. The organic layers were combinedand washed with water 2 times, each time with 200 mL, and thenconcentrated in vacuo to give an oil ethyl4-([1,1′-biphenyl]-4-yl)-3-oxo-2-((R)-1-(triethylsilyloxy)prop-2-yl)-butyrate44.50 g, which was used in the next step without further purification.

Example 9-c: Preparation of(R)-1-([1,1′-biphenyl]-4-yl)-4-methyl-5-(triethylsilyloxy)-2-pentanone

To a 500 mL flask were added 15.00 g of ethyl4-([1,1′-biphenyl]-4-yl)-3-oxo-2-((R)-1-(triethylsilyloxy)prop-2-yl)-butyrateand 130 mL of tetrahydrofuran (THF), the reaction liquid was cooled to0° C., a solution of 4.00 g of lithium hydroxide monohydrate (LiOH.H₂O)in 130 mL of water was added dropwise slowly. After the addition, thereaction liquid was heated to a temperature of 60° C. to 70° C. andstirred for additional 16 hours. After the raw materials were consumedcompletely monitored by HPLC, the reaction liquid was cooled to atemperature of 20° C. to 30° C., 100 mL of 1 N hydrochloric acid wasadded to adjust pH to 2-3, and the reaction liquid was extracted withethyl acetate 3 times, each time with 100 mL. The organic layers werecombined and washed with water 2 times, each time with 200 mL, and thenconcentrated in vacuo to give an oil(R)-1-([1,1′-biphenyl]-4-yl)-4-methyl-5-(triethylsilyloxy)-2-pentanone10.97 g, the yield was 86.9%. ¹H NMR (400 MHz, CDCl₃) δ 7.60 (t, J=7.7Hz, 4H), 7.46 (t, J=7.6 Hz, 2H), 7.40-7.33 (m, 5H), 7.37 (t, J=7.3 Hz,1H), 7.30 (d, J=8.1 Hz, 2H), 3.71 (s, 2H), 3.63 (m, 2H), 3.04-2.94 (m,2H), 2.60-2.51 (m, 1H), 1.36 (m, 6H), 1.18 (m, 12H). ESI-MS (m/z): 383.6([M+H]+).

Example 10. Preparation of(R)-5-([4-iodophenyl])-2-methyl-4-oxopentanoic acid Example 10-a:Preparation of ethyl 4-([4-iodophenyl]-4-yl)-3-oxobutyrate

To a 500 mL three neck flask A were added 200 mL of ethyl acetate and28.64 g of N,N′-carbonyldiimidazole at room temperature, and 25.00 g of4-iodophenyl acetic acid was added in portions to flask A, thegeneration rate of gas was controlled. After the addition, the reactionliquid was heated to 45° C. and reacted for 3 hours, and then cooled toa temperature of 20° C. to 30° C., the flask was evacuated for pressurereduction for 1 hour, and ready for use. To a 1 L flask B were added 280mL of ethyl acetate, 28.06 g of EtO₂CCH₂COOK and 15.70 g of magnesiumchloride (MgCl₂) at room temperature, the temperature was controlled ata temperature of 20° C. to 30° C., and then 19.07 g of triethylamine(TEA) was added dropwise slowly. After the addition, the mixture wasfurther stirred for 1 hour. To flask B was added the materials in flaskA at room temperature, the mixture was heated to 45° C. and reacted for16 hours. The reaction liquid was cooled to a temperature of 20° C. to30° C., and 180 mL of 4 N hydrochloric acid solution was added, and themixture was partitioned, the organic layer was washed three times with250 mL of 6.5% sodium bicarbonate aqueous solution each time, theorganic layers were combined, the solvent was then stripped off in vacuoat 45° C. to give a yellow brown oil. To the obtained oil was added 150mL of n-hexane, the mixture was stirred at 20 to 30° C. for 18 hours andfiltered, the filter cake was washed with n-hexane and dried at atemperature of 40° C. to 50° C. in vacuo for 5 hours to give ethyl4-([4-iodophenyl]-4-yl)-3-oxobutyrate 27.4 g, the yield was 86.5%. 1HNMR (600 MHz, CDCl₃) δ, 7.47 (t, J=7.7 Hz, 2H), 7.33-7.28 (m, 2H),4.25-4.18 (m, 2H), 3.90 (s, 2H), 3.52 (s, 2H), 1.30 (t, J=7.1 Hz, 3H).ESI-MS (m/z): 333.1 ([M+H]+).

Example 10-b: Preparation of (3R)-1-ethyl-4-methyl2-(2-([4-iodophenyl])acetyl)-3-methylsuccinate

To a 500 mL flask were added 5.31 g of sodium hydride (NaH) and 100 mLdried tetrahydrofuran (THF), the flask was degassed and filled withnitrogen 3 times. The reaction liquid was cooled to 0° C., a solution of25.00 g of ethyl 4-([4-iodophenyl]-4-yl)-3-oxobutyrate in 100 mL oftetrahydrofuran (THF) was added dropwise slowly under nitrogen. Afterthe addition, the reaction liquid was heated to a temperature of 20° C.to 30° C. and stirred for additional 30 min. The reaction liquid wascooled to 0° C., and a solution of 31.37 g of (R)-methyl2-(4-methylbenzenesulfonate)propionate in 100 mL of tetrahydrofuran(THF) was added dropwise slowly, after the addition, the reaction liquidwas heated to a temperature of 20° C. to 30° C. and stirred for 1.5hours. After the raw materials were consumed completely monitored byHPLC, to the reaction liquid was added 150 mL of 2 N hydrochloric acidto adjust pH to 2-3, and the reaction liquid was extracted with ethylacetate 3 times, each time with 100 mL. The organic layers were combinedand washed 2 times with 200 mL each time of water, then concentrated invacuo to give an oil (3R)-1-ethyl-4-methyl2-(2-([4-iodophenyl])acetyl)-3-methylsuccinate 48.60 g, which was usedin the next step without further purification.

Example 10-c: Preparation of(R)-5-([4-iodophenyl])-2-methyl-4-oxopentanoic acid

To a 500 mL flask were added 13.00 g of (3R)-1-ethyl-4-methyl2-(2-([4-iodophenyl])acetyl)-3-methylsuccinate and 130 mL oftetrahydrofuran (THF), the reaction liquid was cooled to 0° C., asolution of 3.71 g of lithium hydroxide monohydrate (LiOH.H₂O) in 130 mLof water was added dropwise slowly. After the addition, the reactionliquid was heated to a temperature of 60° C. to 70° C. and stirred foradditional 16 hours. After the raw materials were consumed completelymonitored by HPLC, the reaction liquid was cooled to a temperature of20° C. to 30° C., 100 mL of 1 N hydrochloric acid was added to adjust pHto 2-3, and the reaction liquid was extracted with ethyl acetate 2times, each time with 100 mL. The organic layers were combined andwashed 2 times with 200 mL each time of water, then concentrated to givean oil (R)-5-([4-iodophenyl])-2-methyl-4-oxopentanoic acid 8.46 g, theyield was 82.0%. ¹H NMR (600 MHz, DMSO-d₆) δ 12.16 (s, 1H), 7.66 (d,J=7.3 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H), 3.82 (s, 2H), 2.88 (dd, J=17.7,8.1 Hz, 1H), 2.76-2.69 (m, 1H), 2.61 (dd, J=17.7, 5.4 Hz, 1H), 1.05 (dd,J=16.4, 7.1 Hz, 3H). ESI-MS (m/z): 333.1 ([M+H]+).

Example 11. Preparation of(R)-5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoic acid Example 11-a:Preparation of methyl 4-([1,1′-biphenyl]-4-yl)-3-oxobutyrate

To a 1 L flask were added 20.00 g of 4-biphenylacetic acid, 14.96 g ofMeldrum's acid, 0.61 g of 4-dimethylaminopyridine (DMAP), 21.40 g ofN,N′-dicyclohexylcarbodiimide (DCC) and 200 mL of dichloromethane atroom temperature in turn, the mixture was cooled to 0° C. and stirredfor 12 hours and filtered to remove precipitated solid, the filtrate wasconcentrated to give a light yellow oil. To the above oil was added 150mL of methanol, the mixture was heated to 50° C. under nitrogen, the rawmaterials were consumed completely monitored by TLC, the reaction liquidwas cooled to 0° C. and stirred for 2 hours, and then filtered, thefilter cake was dried at 50° C. in vacuo to give a white solid 23.00 g,the yield was 91%. ¹H NMR (600 MHz, CDCl₃) δ 7.59-7.55 (m, 4H), 7.44 (t,J=7.7 Hz, 2H), 7.37-7.31 (m, 1H), 7.30-7.25 (m, 2H), 3.87 (s, 2H), 3.72(d, J=6.0 Hz, 3H), 3.50 (d, J=10.0 Hz, 2H). ESI-MS (m/z): 269.3([M+H]+).

Example 11-b: Preparation of(3R)-dimethyl-2-(2-([1,1′-biphenyl]-4-yl)acetyl)-3-methylsuccinate

To a 500 mL of flask were added 5.31 g of NaH and 100 mL of dry THF, themixture was degassed and filled with nitrogen 3 times. The reactionliquid was cooled to 0° C., a solution of 25.00 g of methyl4-([1,1′-biphenyl]-4-yl)-3-oxobutyrate in 100 mL of THF was addeddropwise slowly under nitrogen. After the addition, the reaction liquidwas heated to a temperature of 20° C. to 30° C. and stirred foradditional 30 min, and then cooled to 0° C., and a solution of 31.37 gof (R)-methyl-2-(triflate)propionate in 100 mL of tetrahydrofuran wasadded dropwise slowly, after the addition, the reaction liquid washeated to a temperature of 20° C. to 30° C. and stirred for 1.5 hours.After the raw materials were consumed completely monitored by TLC, tothe reaction liquid was added 150 mL of 2 N hydrochloric acid to adjustpH to 2-3, and the reaction liquid was extracted with ethyl acetate 3times. The organic layers were combined and washed with water, and thenconcentrated in vacuo to give an oil 48.60 g, which was used in the nextstep without further purification.

Example 11-c: Preparation of(R)-5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoic acid

To a 500 mL flask were added 15.00 g of(3R)-dimethyl-2-(2-([1,1′-biphenyl]-4-yl)acetyl)-3-methylsuccinate, 130mL of tetrahydrofuran (THF) and 3.71 g of lithium hydroxide. Thereaction liquid was heated to a temperature of 60° C. to 70° C. andstirred for additional 16 hours. After the raw materials were consumedcompletely monitored by TLC, the reaction liquid was cooled to atemperature of 20° C. to 30° C., 100 mL of 1 N hydrochloric acid wasadded to adjust pH to 2-3, and the reaction liquid was extracted withethyl acetate 3 times. The organic layers were combined and washed withwater, and then concentrated in vacuo to give an oil, the oil wasrecrystallized from ethyl acetate and n-hexane (volume rate was 1:1) togive a white solid 7.76 g, the yield was 65%. ¹H NMR (600 MHz, DMSO-d₆)δ 12.16 (s, 1H), 7.66 (d, J=7.3 Hz, 2H), 7.61 (d, J=8.1 Hz, 2H), 7.46(t, J=7.7 Hz, 2H), 7.36 (t, J=7.4 Hz, 1H), 7.28 (d, J=8.1 Hz, 2H), 3.82(s, 2H), 2.88 (dd, J=17.7, 8.1 Hz, 1H), 2.76-2.69 (m, 1H), 2.61 (dd,J=17.7, 5.4 Hz, 1H), 1.05 (dd, J=16.4, 7.1 Hz, 3H). ESI-MS (m/z): 283.3([M+H]+).

First Method of Preparing Sacubitril

Example 12. Preparation of Sacubitril Example 12-a: Preparation of(2R,4S)-5-([1,1′-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid

100 g of isopropylamine was dissolved in 100 mL of water, the mixturewas adjusted with hydrochloric acid aqueous solution to pH 7.5 to 8.0,and then 250 mL of dimethyl sulfoxide (DMSO) was added. The mixture wasdiluted with 0.1 M hydrochloric acidtri(hydroxymethyl)aminomethane-hydrochloric acid(Tris-hydrochloric acid)buffer to a volume of 1000 mL and heated to 40° C., 10 g ofω-transaminase freeze dry powder and 8.0 g of pyridoxal phosphate (PLP)were added, and then a solution of 100 g of(R)-5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoic acid in 250 mL ofdimethyl sulfoxide (DMSO) prepared by the method in example 1 was addeddropwise, 20% isopropylamine aqueous solution was used to control pH 7.5to 8.0 in the reaction process, the temperature was maintained at 40° C.to 45° C. for 24 hours during the reaction procedure, the reaction wasmonitored by TLC until completed. The mixture was filtered to removesolid, and the parent liquid was extracted with ethyl acetate 3 times,the organic layers were combined and concentrated in vacuo to give alight yellow solid 90.2 g, the yield was 90.2%, ee value is 99%. ¹H NMR(600 MHz, DMSO-d₆) δ 8.22 (s, 2H), 7.66 (dd, J=14.2, 7.7 Hz, 4H), 7.47(t, J=7.7 Hz, 2H), 7.36 (t, J=8.0 Hz, 3H), 3.43 (d, J=5.4 Hz, 1H), 3.05(dd, J=13.9, 5.7 Hz, 1H), 2.86 (dd, J=13.9, 7.7 Hz, 1H), 2.66 (m,J=13.9, 7.0 Hz, 1H), 1.86 (m, J=14.2, 8.7, 5.5 Hz, 1H), 1.59 (m, J=13.9,7.7, 5.9 Hz, 1H), 1.07 (d, J=7.0 Hz, 3H). ESI-MS (m/z): 284.3 ([M+H]+).

Example 12-b: Preparation of (2R,4S)-ethyl5-([1,1′-biphenyl]-4-yl)-4-amino-2-methylpentanoate

To a 500 mL flask were added 70.00 g of(2R,4S)-5-([1,1′-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid and 350mL of anhydrous ethanol in turn, the mixture was heated to 40° C. andstirred for dissolution to get a clear solution. To the reaction liquidwas added 32.57 g of thionyl chloride dropwise slowly, after theaddition, the mixture was heated to 70° C. for reaction. After the rawmaterials were consumed completely monitored by HPLC, the reactionsystem was cooled to room temperature slowly and concentrated in vacuoto remove the solvent to give an off-white solid, and to the solid wasadded 630 mL of ethyl acetate, the resulting mixture was heated to 60°C. and stirred for 2 hours, and then cooled to 25° C. and stirred foradditional 2 hours. The mixture was filtered, the filter cake was driedat 50° C. in vacuo to give a white solid 70.77 g, the yield was 92%. ¹HNMR (600 MHz, CDCl₃) δ 8.62 (s, 2H), 7.54 (dd, J=14.1, 7.7 Hz, 4H), 7.41(t, J=7.6 Hz, 2H), 7.36-7.29 (m, 3H), 4.07 (q, J=7.1 Hz, 2H), 3.67 (s,1H), 3.40-3.34 (m, 1H), 2.97 (dd, J=24.3, 10.9 Hz, 2H), 2.07-2.00 (m,1H), 1.90-1.83 (m, 1H), 1.20-1.15 (m, 6H). ESI-MS (m/z): 312.4 ([M+H]+).

Example 12-c: Preparation of Sacubitril

Sacubitril was prepared by the method described in the paragraphs [0038]to [0039] of example 8 of the specification of CN 104557600 A, the yieldwas 91.8%.

¹H NMR (400 MHz, DMSO) δ 7.96 (d, J=8.2 Hz, 1H), 7.62 (d, J=7.4 Hz, 2H),7.55 (d, J=8.1 Hz, 2H), 7.43 (t, J=7.6 Hz, 2H), 7.33 (t, J=7.3 Hz, 1H),7.24 (d, J=8.1 Hz, 2H), 4.02-3.86 (m, 3H), 2.74 (dd, J=13.4, 6.3 Hz,1H), 2.64 (dd, J=13.4, 6.8 Hz, 1H), 2.50-2.44 (m, 1H), 2.26 (dd, J=22.4,7.3 Hz, 4H), 1.81-1.68 (m, 1H), 1.47-1.36 (m, 1H), 1.10 (t, J=7.1 Hz,3H), 1.04 (d, J=7.0 Hz, 3H). ESI-MS (m/z): 412.2 ([M+H]+).

Example 13. Preparation of Sacubitril Example 13-a: Preparation of(2R,4S)-methyl 5-([1,1′-biphenyl]-4-yl)-4-amino-2-methylpentanoate

10 g of isopropylamine was dissolved in 10 mL of water, the mixture wasadjusted with hydrochloric acid aqueous solution to pH 7.5 to 8.0, andthen 25 mL of dimethyl sulfoxide (DMSO) was added. The mixture wasdiluted with 0.1 M hydrochloric acidtri(hydroxymethyl)aminomethane-hydrochloric acid (Tris-hydrochloricacid) buffer to a volume of 100 mL and heated to 40° C., 1.0 g ofω-transaminase freeze dry powder and 0.8 g of pyridoxal phosphate (PLP)were added, and then a solution of 10 g of (R)-methyl5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoate in 25 mL of dimethylsulfoxide (DMSO) prepared by the method in example 2 was added dropwise,20% isopropylamine aqueous solution was used to control pH 7.5 to 8.0 inthe reaction process, the temperature was maintained at 40° C. to 45° C.for 24 hours, the reaction was monitored by TLC until completed. Themixture was filtered to remove solid, and the parent liquid wasextracted with ethyl acetate 3 times, the organic layers were combinedand concentrated in vacuo to give a light yellow solid 8.95 g, the yieldwas 89.6%, ee value was 98.5%. ¹H NMR (600 MHz, DMSO-d₆) δ 8.22 (s, 2H),7.65 (dd, J=14.2, 7.7 Hz, 4H), 7.46 (t, J=7.7 Hz, 2H), 7.36 (t, J=8.0Hz, 3H), 3.68 (s, 3H), 3.43 (d, J=5.4 Hz, 1H), 3.05 (dd, J=13.9, 5.7 Hz,1H), 2.86 (dd, J=13.9, 7.7 Hz, 1H), 2.66 (m, J=13.9, 7.0 Hz, 1H), 1.86(m, J=14.2, 8.7, 5.5 Hz, 1H), 1.59 (m, J=13.9, 7.7, 5.9 Hz, 1H), 1.07(d, J=7.0 Hz, 3H). ESI-MS (m/z): 311.3 ([M+H]+).

Example 13-b: Preparation of(2R,4S)-5-([1,1′-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid

To a 250 mL flask were added 10 g of (2R,4S)-methyl5-([1,1′-biphenyl]-4-yl)-4-amino-2-methylpentanoate, 50 mL oftetrahydrofuran, 50 mL of methanol and 2.41 g of lithium hydroxide inturn, the mixture was stirred at a temperature of 20° C. to 40° C. for12 hours, the reaction was monitored by TLC until completed. The solventwas evaporated in vacuo, to the residue were added 100 mL of water and100 mL of ethyl acetate, and the mixture was stirred for 10 min, theorganic layer was separated and concentrated in vacuo to give a lightyellow solid 8.19 g, the yield was 86%. ¹H NMR (600 MHz, DMSO-d₆) δ 8.22(s, 2H), 7.66 (dd, J=14.2, 7.7 Hz, 4H), 7.47 (t, J=7.7 Hz, 2H), 7.36 (t,J=8.0 Hz, 3H), 3.43 (d, J=5.4 Hz, 1H), 3.05 (dd, J=13.9, 5.7 Hz, 1H),2.86 (dd, J=13.9, 7.7 Hz, 1H), 2.66 (m, J=13.9, 7.0 Hz, 1H), 1.86 (m,J=14.2, 8.7, 5.5 Hz, 1H), 1.59 (m, J=13.9, 7.7, 5.9 Hz, 1H), 1.07 (d,J=7.0 Hz, 3H). ESI-MS (m/z): 284.3 ([M+H]+).

Example 13-c: Preparation of (2R,4S)-ethyl5-([1,1′-biphenyl]-4-yl)-4-amino-2-methylpentanoate

The procedure is the same as the procedure of Example 12-b.

Example 13-d: Preparation of Sacubitril

The procedure is the same as Example 12-c.

Example 14. Preparation of Sacubitril Example 14-a: Preparation of(2R,4S)-ethyl 5-([1,1′-biphenyl]-4-yl)-4-amino-2-methylpentanoate

10 g of isopropylamine was dissolved in 10 mL of water, the mixture wasadjusted with hydrochloric acid aqueous solution to pH 7.5 to 8.0, andthen 25 mL of dimethyl sulfoxide (DMSO) was added. The mixture wasdiluted with 0.1 M hydrochloric acidtri(hydroxymethyl)aminomethane-hydrochloric acid (Tris-hydrochloricacid) buffer to a volume of 100 mL and heated to 40° C., 1.0 g ofω-transaminase freeze dry powder and 0.8 g of pyridoxal phosphate (PLP)were added, and then a solution of 10 g of (R)-ethyl5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoate in 25 mL of dimethylsulfoxide (DMSO) prepared by the method in example 3 was added dropwise,20% isopropylamine aqueous solution was used to control pH 7.5 to 8.0 inthe reaction process, the temperature was maintained at 40° C. to 45° C.for 24 hours, the reaction was monitored by TLC until completed. Themixture was filtered to remove solid, and the parent liquid wasextracted with ethyl acetate 3 times, the organic layers were combinedand concentrated in vacuo to give a light yellow solid 8.80 g, the yieldwas 88.1%, ee value was 99.0%. ¹H NMR (600 MHz, CDCl₃) δ 8.62 (s, 2H),7.54 (dd, J=14.1, 7.7 Hz, 4H), 7.41 (t, J=7.6 Hz, 2H), 7.36-7.29 (m,3H), 4.07 (q, J=7.1 Hz, 2H), 3.67 (s, 1H), 3.40-3.34 (m, 1H), 2.97 (dd,J=24.3, 10.9 Hz, 2H), 2.07-2.00 (m, 1H), 1.90-1.83 (m, 1H), 1.20-1.15(m, 6H). ESI-MS (m/z): 312.4 ([M+H]+).

Example 14-b: Preparation of Sacubitril

The procedure is the same as the procedure of Example 12-c.

Example 15. Preparation of Sacubitril Example 15-a: Preparation of(2R,4S)-isopropyl 5-([1,1′-biphenyl]-4-yl)-4-amino-2-methylpentanoate

10 g of isopropylamine was dissolved in 10 mL of water, the mixture wasadjusted with hydrochloric acid aqueous solution to pH 7.5 to 8.0, andthen 25 mL of dimethyl sulfoxide (DMSO) was added. The mixture wasdiluted with 0.1 M hydrochloric acidtri(hydroxymethyl)aminomethane-hydrochloric acid (Tris-hydrochloricacid) buffer to a volume of 100 mL and heated to 40° C., 1.0 g ofω-transaminase freeze dry powder and 0.8 g of pyridoxal phosphate (PLP)were added, and then a solution of 10 g of (R)-isopropyl5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoate in 25 mL of dimethylsulfoxide (DMSO) prepared by the method in example 4 was added dropwise,20% isopropylamine aqueous solution was used to control pH 7.5-8.0 inthe reaction process, the temperature was maintained at 40-45° C. for 24hours, the reaction was monitored by TLC until completed. The mixturewas filtered to remove solid, and the parent liquid was extracted withethyl acetate 3 times, the organic layers were combined and concentratedin vacuo to give a light yellow solid 8.20 g, the yield was 82.1%, eevalue was 96.5%. ¹H NMR (600 MHz, CDCl₃) δ 8.62 (s, 2H), 7.54 (dd,J=14.1, 7.7 Hz, 4H), 7.41 (t, J=7.6 Hz, 2H), 7.36-7.29 (m, 3H), 4.93 (m,1H), 3.67 (s, 1H), 3.40-3.34 (m, 1H), 2.97 (dd, J=24.3, 10.9 Hz, 2H),2.07-2.00 (m, 1H), 1.90-1.83 (m, 1H), 1.31 (d, J=7.1 Hz, 6H), 1.17 (d,J=6.8 Hz, 3H). ESI-MS (m/z): 326.4 ([M+H]+).

Example 15-b: Preparation of(2R,4S)-5-([1,1′-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid

To a 250 mL flask were added 10 g of (2R,4S)-isopropyl5-([1,1′-biphenyl]-4-yl)-4-amino-2-methylpentanoate, 50 mL oftetrahydrofuran, 50 mL of methanol and 2.65 g of sodium hydroxide inturn, the mixture was stirred at a temperature of 20° C. to 40° C. for12 hours, the reaction was monitored by TLC until completed. The solventwas evaporated in vacuo, to the residue were added 100 mL of water and100 mL of ethyl acetate, and the mixture was stirred for 10 min, theorganic layer was separated and concentrated in vacuo to give a lightyellow solid 7.40 g, the yield was 85%. ¹H NMR (600 MHz, DMSO-d₆) δ 8.22(s, 2H), 7.66 (dd, J=14.2, 7.7 Hz, 4H), 7.47 (t, J=7.7 Hz, 2H), 7.36 (t,J=8.0 Hz, 3H), 3.43 (d, J=5.4 Hz, 1H), 3.05 (dd, J=13.9, 5.7 Hz, 1H),2.86 (dd, J=13.9, 7.7 Hz, 1H), 2.66 (m, J=13.9, 7.0 Hz, 1H), 1.86 (m,J=14.2, 8.7, 5.5 Hz, 1H), 1.59 (m, J=13.9, 7.7, 5.9 Hz, 1H), 1.07 (d,J=7.0 Hz, 3H). ESI-MS (m/z): 284.3 ([M+H]+).

Example 15-c: Preparation of (2R,4S)-ethyl5-([1,1′-biphenyl]-4-yl)-4-amino-2-methylpentanoate

The procedure is the same as the procedure of Example 12-b.

Example 15-d: Preparation of Sacubitril

The procedure is the same as the procedure of Example 12-c.

Example 16. Preparation of Sacubitril Example 16-a: Preparation of(2R,4S)-benzyl 5-([1,1′-biphenyl]-4-yl)-4-amino-2-methylpentanoate

10 g of isopropylamine was dissolved in 10 mL of water, the mixture wasadjusted with hydrochloric acid aqueous solution to pH 7.5 to 8.0, andthen 25 mL of dimethyl sulfoxide (DMSO) was added. The mixture wasdiluted with 0.1 M hydrochloric acidtri(hydroxymethyl)aminomethane-hydrochloric acid (Tris-hydrochloricacid) buffer to a volume of 100 mL and heated to 40° C., 1.0 g ofω-transaminase freeze dry powder and 0.8 g of pyridoxal phosphate (PLP)were added, and then a solution of 10 g of (R)-benzyl5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoate in 25 mL of dimethylsulfoxide (DMSO) prepared by the method in example 5 was added dropwise,20% isopropylamine aqueous solution was used to control pH 7.5-8.0 inthe reaction process, the temperature was maintained at 40-45° C. for 24hours, the reaction was monitored by TLC until completed. The mixturewas filtered to remove solid, and the parent liquid was extracted withethyl acetate 3 times, the organic layers were combined and concentratedin vacuo to give a light yellow solid 7.90 g, the yield was 79.1%, eevalue was 88.0%. ¹H NMR (600 MHz, CDCl₃) δ 8.62 (s, 2H), 7.54 (dd,J=14.1, 7.7 Hz, 4H), 7.41 (t, J=7.6 Hz, 2H), 7.40-7.33 (m, 5H),7.36-7.29 (m, 3H), 5.22 (s, 2H), 3.67 (s, 1H), 3.40-3.34 (m, 1H), 2.97(dd, J=24.3, 10.9 Hz, 2H), 2.07-2.00 (m, 1H), 1.90-1.83 (m, 1H), 1.15(d, J=6.8 Hz, 3H). ESI-MS (m/z): 374.4 ([M+H]+).

Example 16-b: Preparation of(2R,4S)-5-([1,1′-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid

To a 250 mL flask were added 10 g of (2R,4S)-benzyl5-([1,1′-biphenyl]-4-yl)-4-amino-2-methylpentanoate, 50 mL oftetrahydrofuran, 50 mL of methanol and 2.65 g of sodium hydroxide inturn, the mixture was stirred at the mixture of 20° C. to 40° C. for 12hours, the reaction was monitored by TLC until completed. The solventwas evaporated in vacuo, to the residue were added 100 mL of water and100 mL of ethyl acetate, and the mixture was stirred for 10 min, theorganic layer was separated and concentrated in vacuo to give a lightyellow solid 6.22 g, the yield was 82%. ¹H NMR (600 MHz, DMSO-d₆) δ 8.22(s, 2H), 7.66 (dd, J=14.2, 7.7 Hz, 4H), 7.47 (t, J=7.7 Hz, 2H), 7.36 (t,J=8.0 Hz, 3H), 3.43 (d, J=5.4 Hz, 1H), 3.05 (dd, J=13.9, 5.7 Hz, 1H),2.86 (dd, J=13.9, 7.7 Hz, 1H), 2.66 (m, J=13.9, 7.0 Hz, 1H), 1.86 (m,J=14.2, 8.7, 5.5 Hz, 1H), 1.59 (m, J=13.9, 7.7, 5.9 Hz, 1H), 1.07 (d,J=7.0 Hz, 3H). ESI-MS (m/z): 284.3 ([M+H]+).

Example 16-c: Preparation of (2R,4S)-ethyl5-([1,1′-biphenyl]-4-yl)-4-amino-2-methylpentanoate

The procedure is the same as the procedure of Example 12-b.

Example 16-d: Preparation of Sacubitril

The procedure is the same as Example 12-c.

Example 17. Second Method of Preparing Sacubitril Example 17 Preparationof Sacubitril Example 17-a: Preparation of(3R,6R,7aR)-7a-([1,1′-biphenyl]-4-yl-methyl)-6-methyl-3-phenyltetrahydropyrrolo-[2,1-b]oxazole-5(6H)-one

To a 250 mL flask were added 5.90 g of(R)-5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoic acid prepared bythe method in example 11, 3.42 g of D-phenylglycinol and 60 mL oftoluene, the mixture was heated to 125° C. with stirring and reacted for13 hours. The raw materials were consumed monitored by TLC, the reactionliquid was cooled to a temperature of 20° C. to 30° C. and concentratedin vacuo to give an oil 7.37 g, the yield was 92%. ¹H NMR (600 MHz,CDCl₃) δ 7.61 (dd, J=8.2, 7.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 7.49-7.40(m, 6H), 7.39-7.32 (m, 2H), 7.30-7.27 (m, 2H), 5.30 (t, J=7.5 Hz, 1H),4.73 (t, J=8.4 Hz, 1H), 4.45 (dd, J=8.8, 7.1 Hz, 1H), 3.09 (d, J=13.9Hz, 1H), 2.96 (d, J=13.9 Hz, 1H), 2.69 (dd, J=12.8, 8.3 Hz, 1H),2.61-2.51 (m, 1H), 1.74 (t, J=12.1 Hz, 1H), 1.16 (d, J=7.1 Hz, 3H).ESI-MS (m/z): 384.4 ([M+H]+).

Example 17-b: Preparation of(3R,5S)-5-([1,1′-biphenyl-4-yl-methyl)-1-((R)-2-hydroxy-1-phenylethyl)-3-methyl-2-pyrrolidone

To a 250 mL three neck flask were added 8.02 g of(3R,6R,7aR)-7a-([1,1′-biphenyl]-4-yl-methyl)-6-methyl-3-phenylphenyltetrahydropyrrolo-[2,1-b]oxazole-5(6H)-oneand 80 mL of toluene in turn, 7.29 g of triethyl silicane was added tothe mixture under nitrogen, the mixture was cooled to −35° C., and 42 mLof titanium tetrachloride in toluene was added dropwise slowly. Afterthe addition, the mixture was stirred for 12 hours. After the rawmaterials were consumed as monitored by TLC, to the reaction mixture wasadded 350 mL of 25% ammonium chloride aqueous solution. The organiclayer was separated and concentrated in vacuo to give an oil 6.05 g, theyield was 75%. ¹H NMR (600 MHz, CDCl₃) δ 7.56 (d, J=7.4 Hz, 2H), 7.48(d, J=8.1 Hz, 2H), 7.47-7.40 (m, 4H), 7.40-7.34 (m, 4H), 7.01 (d, J=8.0Hz, 2H), 4.89 (dd, J=8.0, 4.3 Hz, 1H), 4.19 (dd, J=11.6, 4.3 Hz, 1H),3.78-3.72 (m, 2H), 3.51 (t, J=6.7 Hz, 1H), 3.13 (dd, J=13.0, 3.9 Hz,1H), 2.61-2.51 (m, 1H), 2.24 (dd, J=12.8, 11.0 Hz, 1H), 2.19 (ddd,J=13.0, 8.9, 6.9 Hz, 1H), 1.32 (d, J=7.1 Hz, 3H). ESI-MS (m/z): 386.3([M+H]+).

Example 17-c: Preparation of(3R,5S)-3-methyl-5-([1,1′-biphenyl]-4-yl-methyl)-2-pyrrolidone

To a 250 mL hydrogenation reaction flask were added 7.00 g of(3R,5S)-5-([1,1′-biphenyl-4-yl-methyl)-1-((R)-2-hydroxy-1-phenylethyl)-3-methyl-2-pyrrolidone,3.50 g of 10% Pd/C and 70 mL of methanol, the system was degassed andfilled with nitrogen 3 times, and the pressure with hydrogen was to 4Mpa at room temperature, the mixture was heated to 80° C. with stirringand reacted for 24 h. The raw materials were consumed monitored by TLC,the mixture was filtered, and the catalyst was recovered, the filtratewas concentrated in vacuo, the residue was recrystallized from ethylacetate and n-hexane (volume rate was 1:1) to give a white solid 4.29 g,the yield was 89%. ¹H NMR (400 MHz, CDCl₃) δ 7.63-7.53 (m, 4H), 7.46 (t,J=7.6 Hz, 2H), 7.37 (t, J=7.3 Hz, 1H), 7.30-7.24 (m, 3H), 5.75 (s, 1H),3.92-3.82 (m, 1H), 2.88 (dd, J=13.4, 5.5 Hz, 1H), 2.77 (dd, J=13.4, 8.4Hz, 1H), 2.58-2.46 (m, 1H), 2.18 (dt, J=12.5, 7.2 Hz, 1H), 1.96 (dt,J=12.9, 7.8 Hz, 1H), 1.22 (d, J=7.2 Hz, 3H). ESI-MS (m/z): 266.1([M+H]+)

Example 17-d: Preparation of (2R,4S)-ethyl5-([1,1′-biphenyl]-4-yl)-4-amino-2-methylpentanoate hydrochloride

To a 100 mL hydrogenation reaction flask were added 0.65 g of(3R,5S)-3-methyl-5-([1,1′-biphenyl]-4-yl-methyl)-2-pyrrolidone, 20 mL ofmethanol and 2 mL of concentrated hydrochloric acid, the mixture washeated to a temperature of 70° C. to 85° C. with stirring and reactedfor 24 h. The raw materials were consumed monitored by TLC, the mixturewas concentrated in vacuo, the residue was recrystallized from ethylacetate to give a white solid 0.70 g, the yield was 82%. ¹H NMR (600MHz, CDCl₃) δ 8.62 (s, 3H), 7.54 (dd, J=14.1, 7.7 Hz, 4H), 7.41 (t,J=7.6 Hz, 2H), 7.36-7.29 (m, 3H), 4.07 (q, J=7.1 Hz, 2H), 3.67 (s, 1H),3.40-3.34 (m, 1H), 2.97 (dd, J=24.3, 10.9 Hz, 2H), 2.07-2.00 (m, 1H),1.90-1.83 (m, 1H), 1.20-1.15 (m, 6H). ESI-MS (m/z): 312.1 ([M+H]⁺

Example 17-e: Preparation of Sacubitril

The procedure is the same as the procedure of Example 12-c.

Example 18. Preparation of Sacubitril Example 18-a: Preparation of(3R,6R,7aR)-7a-([1,1′-biphenyl]-4-yl-methyl)-6-methyl-3-phenyltetrahydropyrrolo-[2,1-b]oxazole-5(6H)-one

To a 250 mL flask were added 6.50 g of (R)-methyl5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoate prepared by the methodin example 2, 3.70 g of D-phenylglycinol and 70 mL of toluene, themixture was heated to 125° C. with stirring and reacted for 13 hours.The raw materials were consumed monitored by TLC, the reaction liquidwas cooled to a temperature of 20° C. to 30° C. and concentrated invacuo to give an oil 7.23 g, the yield was 86%. ¹H NMR (600 MHz, CDCl₃)δ 7.61 (dd, J=8.2, 7.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 7.49-7.40 (m,6H), 7.39-7.32 (m, 2H), 7.30-7.27 (m, 2H), 5.30 (t, J=7.5 Hz, 1H), 4.73(t, J=8.4 Hz, 1H), 4.45 (dd, J=8.8, 7.1 Hz, 1H), 3.09 (d, J=13.9 Hz,1H), 2.96 (d, J=13.9 Hz, 1H), 2.69 (dd, J=12.8, 8.3 Hz, 1H), 2.61-2.51(m, 1H), 1.74 (t, J=12.1 Hz, 1H), 1.16 (d, J=7.1 Hz, 3H). ESI-MS (m/z):384.4 ([M+H]+).

Example 18-b: Preparation of(3R,5S)-5-([1,1′-biphenyl-4-yl-methyl)-1-((R)-2-hydroxy-1-phenylethyl)-3-methyl-2-pyrrolidone

The procedure is the same as the procedure of Example 17-b.

Example 18-c: Preparation of(3R,5S)-3-methyl-5-([1,1′-biphenyl]-4-yl-methyl)-2-pyrrolidone

The procedure is the same as the procedure of Example 17-c.

Example 18-d: Preparation of (2R,4S)-ethyl5-([1,1′-biphenyl]-4-yl)-4-amino-2-methylpentanoate hydrochloride

The procedure is the same as the procedure of Example 17-d.

Example 18-e: Preparation of Sacubitril

The procedure is the same as the procedure of Example 12-c.

As described in the above examples, the synthesis method provided hereincan efficiently prepare the compound of Formula (V), and furthersynthesize sacubitril from the compound of Formula (V). The methoddisclosed herein has advantages of easily obtained raw materials, simplepreparation process, low cost and environment friendly, and so on.

The method of the invention has been described by the preferredembodiment. Related person can clearly realize and apply the techniquesdisclosed herein by making some changes, appropriate alterations orcombinations to the methods without departing from spirit, principlesand scope of the present disclosure. Skilled in the art can learn fromthis article to properly improve the process parameters to implement thepreparation method. Of particular note is that all similar substitutionsand modifications to the skilled person are obvious, and they are deemedto be included in the present invention.

What is claimed is:
 1. A method of preparing sacubitril,

comprising the following steps: a) preparing a compound of Formula (VI)by an enzymic catalytic reaction of a compound of Formula (V) in thepresence of ω-transaminase and phosphopyridoxal,

b) optionally, preparing a compound of Formula (VII) from the compoundof Formula (VI):

c) preparing sacubitril from the compound of Formula (VII), wherein: R₁is phenyl, methoxy, hydroxy, chloro, bromo, iodo, mesylate, triflate or4-methylbenzenesulfonate; R₂ is

R₃ is H, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl; and R₄ is H,—(C₁-C₄)alkyl, —(C₃-C₆)heterocyclyl, —(C₁-C₄)alkyl-aryl, trimethylsilyl,triethylsilyl or t-butyldimethylsilyl.
 2. The method of claim 1, whereinthe compound of Formula (V) is prepared by a deprotection reaction of acompound of Formula (IV):

in the presence of a base or an acid, wherein: R₁ is phenyl, methoxy,hydroxy, chloro, bromo, iodo, mesylate, triflate or4-methylbenzenesulfonate; R₂ is

 and when R₁ is phenyl, R₂ is not

R₃ is H, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl; R₄ is H, —(C₁-C₄)alkyl,—(C₃-C₆)heterocyclyl, —(C₁-C₄)alkyl-aryl, trimethylsilyl, triethylsilylor t-butyldimethylsilyl; and R₅ is H, —(C₁-C₄)alkyl or—(C₁-C₄)alkyl-aryl.
 3. The method of claim 2, compound of Formula (IV)is prepared by a substitution reaction of a compound of Formula (II)with a compound of Formula (III) in the presence of a base;


4. The method of claim 3, compound of Formula (II) is prepared by acondensation reaction of a compound of Formula (I);

wherein R₁ is as defined above; and R₅ is H, —(C₁-C₄)alkyl or—(C₁-C₄)alkyl-aryl.
 5. The method according to claim 2, wherein thecompound of the Formula (IV) is prepared by a process comprising thefollowing steps: a) preparing a compound of Formula (II) by acondensation reaction of a compound of Formula (I) in the presence of abase,

b) preparing a compound of Formula (IV) by a substitution reaction ofthe compound of Formula (II) with a compound of Formula (III) in thepresence of a strong base;

wherein R₁ is phenyl; R₂ is

R₃ is H, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl or benzyl;R₄ is H, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, benzyl,trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triphenylmethyl,tetrahydrofuryl; R₅ is H, methyl, ethyl, n-propyl, i-propyl, n-butyl orbenzyl; and R₆ is triflate, mesylate or 4-methylbenzenesulfonate.
 6. Themethod of claim 5 wherein the compound of Formula (II) is prepared by acondensation reaction of the compound of Formula (I) withN,N′-carbonyldiimidazole and a compound of Formula (VIII):

in the presence of magnesium chloride and triethylamine, wherein R₅ isH, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl.
 7. The method of claim 5,wherein the compound of Formula (II) is prepared by a condensationreaction of the compound of Formula (I) with Meldrum's acid,4-dimethylaminopyridine, R₅OH and pivaloyl chloride in the presence ofN,N-diisopropylethylamine, R₅ is H, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl.8. The method of claim 1, wherein R₁ is phenyl; R₂ is

and R₃ is methyl, ethyl, propyl, i-propyl, n-butyl, t-butyl, benzyl oroptionally substituted benzyl.
 9. The method of claim 1, comprising thefollowing steps: a) preparing a compound of Formula (VII) by an enzymiccatalytic reaction of a compound of Formula (V):

in the presence of ω-transaminase and phosphopyridoxal; and b) preparingsacubitril by an amide condensation reaction of the compound of Formula(VII) with succinic anhydride, wherein R₁ is phenyl, and R₂ is

and R₃ is ethyl.
 10. The method of preparing sacubitril of claim 1,wherein the compound of Formula (VII) is prepared by a hydrolysisreaction of the compound of Formula (VI) and then an esterificationreaction of the hydrolysis product with ethanol.
 11. The method of claim1, wherein the compound of the Formula (VII) is prepared by a processcomprising the following steps: a) preparing a compound of Formula (X)by a reaction of a compound of Formula (V) with a compound of Formula(IX),

b) preparing a compound of Formula (XI) from the compound of Formula(X),

c) preparing a compound of Formula (XII) from the compound of Formula(XI),

d) preparing a compound of Formula (VII) from the compound of Formula(XII),

wherein: R₁ is phenyl, methoxy, hydroxy, chloro, bromo, iodo, mesylate,triflate or 4-methylbenzenesulfonate; R₂ is

R₃ is H, —(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl; and R₇ is phenyl,—(C₁-C₄)alkyl or —(C₁-C₄)alkyl-aryl.
 12. The method of claim 11, whereinthe compound of Formula (IX) in step a) is D-phenylglycinol.
 13. Themethod of claim 11, wherein the compound of Formula (XI) is preparedfrom the compound of Formula (X) in the presence of titaniumtetrachloride and triethyl silicane in step b).
 14. The method of claim11, wherein the compound of Formula (XII) is prepared from the compoundof Formula (XI) in the presence of palladium-carbon in step c).
 15. Themethod of claim 11, wherein the compound of Formula (VII) is preparedfrom the compound of Formula (XII) in ethanol in the presence of an acidin step d).
 16. The method of claim 11, wherein the compound of theFormula (VII) is prepared by a process comprising the following steps:a) preparing a compound of Formula (XIII) by a reaction of(R)-5-([1,1′-biphenyl]-4-yl)-2-methyl-4-oxopentanoic acid withD-phenylglycinol,

b) preparing a compound of Formula (XIV) from the compound of Formula(XIII) in the presence of titanium tetrachloride and triethyl silicane,

c) preparing a compound of Formula (XII) from the compound of Formula(XIV) in the presence of palladium-carbon,

d) preparing a compound of Formula (VII) by a ring opening reaction ofthe compound of Formula (XII):